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T cell

T cells, also known as T lymphocytes, are a subset of white blood cells that play a central role in the adaptive immune system of vertebrates by mediating cell-mediated immunity.^[1] They originate from hematopoietic stem cells in the bone marrow and migrate to the thymus, where they undergo maturation through a stepwise process involving positive and negative selection to ensure recognition of foreign antigens while maintaining self-tolerance.^[2] Mature T cells express a unique T-cell receptor (TCR) on their surface, which specifically recognizes peptide antigens presented by major histocompatibility complex (MHC) molecules on the surface of other cells.^[3] T cells are broadly classified into subsets based on function and surface markers, including CD4+ helper T cells, which coordinate immune responses by activating other immune cells such as B cells and macrophages through cytokine production; CD8+ cytotoxic T cells, which directly kill virus-infected or cancerous cells; and regulatory T cells (Tregs), which suppress excessive immune reactions to prevent autoimmunity and maintain tolerance.^[4] Additional subsets include memory T cells, which provide long-term immunity by rapidly responding to previously encountered pathogens, and effector T cells that mediate immediate defense.^[5] Throughout life, T cells localize to lymphoid organs, mucosal tissues, and peripheral sites, adapting their functions to combat infections, allergens, and tumors while influencing overall immune homeostasis.^[2]

Structure and Markers

Morphology and Ultrastructure

T cells, in their naive state, are small, round lymphocytes measuring approximately 7–10 μm in diameter, characterized by a thin rim of cytoplasm surrounding a large, centrally located nucleus that occupies the majority of the cell volume, resulting in a high nucleus-to-cytoplasm ratio.^[1]^[6] The cytoplasm in naive T cells contains minimal endoplasmic reticulum, reflecting low protein synthetic activity, along with few mitochondria, sparse ribosomes, and limited lysosomes, which support their quiescent metabolic profile.^[1]^[7] Upon activation by antigenic stimuli, T cells undergo blast transformation, markedly increasing in size to 10–15 μm in diameter with substantial cytoplasmic expansion to accommodate heightened biosynthetic demands.^[6]^[8] This activation-induced morphological shift includes proliferation of organelles, notably the expansion of the Golgi apparatus to facilitate cytokine packaging and secretion via the classical endoplasmic reticulum-Golgi pathway.^[1]^[9] Ultrastructurally, T cells exhibit a dynamic cytoskeleton comprising microtubules and actin microfilaments that underpin cellular motility and shape maintenance, with microtubules organizing intracellular transport and microfilaments supporting membrane protrusions such as microvilli for antigen scanning.^[10]^[11] These features, observable via electron microscopy, highlight the T cell's adaptability from a compact, resting form to an enlarged, effector-ready state.^[11]

Surface Receptors and Markers

T cells express a variety of surface receptors and markers that are essential for their identification, signaling, and interactions with other cells in the immune system. These molecules include the CD3 complex, co-receptors such as CD4 and CD8, and additional markers like CD45, CD28, and integrins, which collectively define T cell subsets and functional states.^[12] Flow cytometry relies on these markers to distinguish between naive, memory, and activated T cells, enabling precise characterization of T cell populations.^[13] The CD3 complex serves as an invariant signaling subunit noncovalently associated with the T cell receptor (TCR), facilitating signal transduction upon antigen recognition. It is composed of three dimers: CD3εγ, CD3εδ, and the homodimer CD3ζζ, totaling six CD3 chains that are critical for the assembly and surface expression of the TCR-CD3 complex.^[14] The ζ chains, in particular, contain immunoreceptor tyrosine-based activation motifs (ITAMs) that become phosphorylated to initiate downstream signaling cascades.^[12] CD4 and CD8 act as co-receptors that enhance TCR signaling by binding to major histocompatibility complex (MHC) molecules on antigen-presenting cells. CD4 specifically interacts with the β2 domain of MHC class II molecules, recruiting the kinase Lck to amplify TCR-mediated signals in helper T cells.^[15] In contrast, CD8 binds to the α3 domain of MHC class I molecules, stabilizing the TCR-pMHC interaction and similarly facilitating Lck recruitment in cytotoxic T cells.^[16] These co-receptors are mutually exclusive on individual T cells, defining the helper (CD4+) and cytotoxic (CD8+) lineages.^[15] Other key surface markers include CD45, a transmembrane protein tyrosine phosphatase expressed in multiple isoforms due to alternative splicing of its extracellular domain. CD45 isoforms, such as CD45RA and CD45RO, exhibit phosphatase activity that regulates T cell signaling by dephosphorylating inhibitory sites on kinases like Lck, thereby modulating activation thresholds.^[17] CD28 provides co-stimulatory signals essential for full T cell activation, binding to B7 ligands (CD80/CD86) on antigen-presenting cells to promote cytokine production and prevent anergy.^[18] Integrins like LFA-1 (lymphocyte function-associated antigen 1, composed of αLβ2 subunits) mediate adhesion to intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and antigen-presenting cells, supporting T cell migration and stable immunological synapses.^[19] In flow cytometry, T cell subsets are identified using these markers: naive T cells are characterized by high expression of CD45RA, reflecting their unprimed state, while memory T cells express CD45RO, an isoform associated with prior antigen exposure.^[13] Activated T cells upregulate CD25, the α-chain of the high-affinity interleukin-2 receptor (IL-2R), which enhances responsiveness to IL-2 and sustains proliferation during immune responses.^[20] These markers allow for the discrimination of functional T cell states in both research and clinical settings.^[13]

Development

Hematopoietic Origin and Thymic Migration

T cells originate from hematopoietic stem cells (HSCs) residing in the bone marrow, where these multipotent cells differentiate into various blood cell lineages.^[21] HSCs first generate common lymphoid progenitors (CLPs), which are committed to the lymphoid lineage and serve as precursors for T cells, B cells, and natural killer cells.^[21] The CLP stage is characterized by the expression of markers such as IL-7 receptor alpha (IL-7Rα) and the absence of myeloid-specific markers, marking the initial restriction from myeloid potential.^[21] From the bone marrow, early T cell precursors (ETPs), derived from CLPs or closely related progenitors, seed the thymus.00288-9) ETPs are defined by their Lin⁻ (lineage marker-negative) phenotype, high expression of CD117 (c-Kit), and positivity for CD44, while lacking expression of CD4 and CD8 coreceptors.^[22] These double-negative (DN) cells represent the most immature thymic progenitors capable of multilineage differentiation, including limited myeloid and dendritic cell potential before full T lineage commitment.00288-9) ETPs migrate from the bone marrow to the thymus cortex primarily through the bloodstream, guided by chemokine signaling.^[23] The key axes involve the receptor CCR7 on progenitors responding to ligands CCL19 and CCL21 produced in the thymic cortex, which direct homing and initial entry.^[23] A complementary pathway uses CCR9 and CCL25 for vascular crossing at the corticomedullary junction, ensuring efficient precursor recruitment.^[23] Upon entering the thymus, ETPs rely on the thymic microenvironment for survival and early expansion.^[24] Cortical epithelial cells provide essential signals, including IL-7, to support progenitor proliferation and prevent apoptosis.^[25] Mesenchymal stromal cells in the perivascular regions contribute by producing extracellular matrix components and additional growth factors, fostering a niche that sustains these early immigrants before further differentiation.^[26]

T Cell Receptor Rearrangement

T cell receptor (TCR) genes undergo V(D)J recombination in developing thymocytes to generate a diverse repertoire capable of recognizing a wide array of antigens. This somatic recombination process assembles variable (V), diversity (D), and joining (J) gene segments, primarily mediated by the recombination-activating genes RAG1 and RAG2, which recognize recombination signal sequences (RSSs) flanking these segments and introduce double-strand breaks at their borders. The RAG1/RAG2 complex forms a synaptic complex with the DNA, cleaving it to produce hairpin coding ends and blunt signal ends, which are then processed and joined by non-homologous end joining (NHEJ) machinery, including proteins like Ku70/80, DNA-PKcs, Artemis, XRCC4, and ligase IV.90760-5)^[27]^[28] Rearrangement begins at the TCRβ locus during the double-negative (DN) stage of thymocyte development, specifically in DN2/DN3 cells. Initial Dβ-to-Jβ joining occurs on both alleles, followed by Vβ-to-DJβ recombination, which is attempted sequentially on one allele at a time. A productive in-frame rearrangement yields a functional TCRβ chain, which pairs with the invariant pre-Tα (pTα) chain and CD3 signaling components to form the pre-T cell receptor (pre-TCR) complex. Signaling through the pre-TCR, often ligand-independently via autonomous dimerization, triggers β-selection: a checkpoint that promotes cell survival, proliferation (yielding 10-100 daughter cells per precursor), differentiation to the DN4 and double-positive (DP) stage, and enforcement of allelic exclusion to prevent further TCRβ rearrangements on the other allele.^[28]^[29] TCRα rearrangement follows in the DP stage, after β-selection, and involves only Vα-to-Jα joining, as there is no D segment. Unlike TCRβ, TCRα loci permit multiple sequential attempts, with secondary rearrangements excising prior V-J joins via upstream Vα segments recombining with downstream Jα segments, allowing replacement until a functional chain is produced. Allelic exclusion for TCRα is less stringent, achieved primarily through post-transcriptional and selection mechanisms rather than strict feedback inhibition, ensuring most mature T cells express a single functional αβ TCR heterodimer. This sequential process—β first, then α—maximizes diversity while minimizing non-productive outcomes.^[28]^[30]^[31] Junctional diversity at the V(D)J junctions further amplifies TCR variability, contributing more to the repertoire than combinatorial joining alone. During recombination, coding ends undergo exonucleolytic nibbling (nucleotide removal) and palindromic (P) nucleotide additions from hairpin resolution, while non-templated N-nucleotides are randomly added by terminal deoxynucleotidyl transferase (TdT), an enzyme expressed in DN and early DP thymocytes. TdT adds 0-15 untemplated nucleotides (primarily G/C-rich) to the 3' ends of coding segments before ligation, with TCRβ junctions averaging 2-3 N-nucleotides and TCRα averaging more due to prolonged TdT expression. In TdT-deficient mice, N-additions are absent, reducing junctional diversity by up to 90% in adult T cells, underscoring TdT's role in generating high-affinity TCRs for peripheral challenges.^[32]^[28]^[33]

Thymic Selection

Thymic selection encompasses the dual processes of positive and negative selection, which shape the T cell repertoire in the thymus to ensure functionality and self-tolerance. Developing thymocytes, having undergone T cell receptor (TCR) gene rearrangement, undergo these selections to filter out non-functional or autoreactive clones, resulting in mature T cells that recognize foreign antigens presented by self-major histocompatibility complex (MHC) molecules. This selection occurs sequentially in the thymic cortex and medulla, involving interactions with specialized antigen-presenting cells that present self-peptides on MHC.^[34] Positive selection occurs in the thymic cortex and rescues double-positive (CD4⁺CD8⁺) thymocytes from programmed cell death by recognizing low-affinity self-peptide-MHC complexes. These interactions primarily involve cortical thymic epithelial cells (cTECs), which uniquely express proteases that generate a distinct peptide repertoire for presentation on MHC class I and II molecules. Thymocytes whose TCRs bind MHC class II receive signals promoting CD4 lineage commitment, while those binding MHC class I commit to the CD8 lineage, yielding single-positive thymocytes capable of antigen recognition restricted to self-MHC—a principle established by foundational experiments demonstrating that cytotoxic T cells respond only to antigens presented in the context of syngeneic MHC.^[34]^[35] Only about 1-5% of double-positive thymocytes survive positive selection, highlighting its stringent nature in establishing a restricted yet diverse repertoire.^[34] Following positive selection, single-positive thymocytes migrate to the thymic medulla for negative selection, where high-affinity binding to self-peptide-MHC complexes induces apoptosis in autoreactive clones. This process is mediated by medullary thymic epithelial cells (mTECs), dendritic cells, and macrophages, which collectively present a broad array of self-antigens to ensure central tolerance. A key regulator is the autoimmune regulator (AIRE) transcription factor, expressed predominantly in mTECs, which orchestrates the promiscuous expression of thousands of tissue-restricted antigens (TRAs), enabling the deletion of T cells reactive to peripheral self-tissues that would otherwise escape thymic surveillance. Defects in AIRE, as seen in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), lead to impaired negative selection and multi-organ autoimmunity, underscoring its essential role. Negative selection thus complements positive selection by eliminating threats to self-tolerance while preserving the MHC-restricted functionality of the T cell pool.^[34]

Peripheral Maturation and Homeostasis

Upon exiting the thymus, recent thymic emigrants (RTEs), identified as CD31+ naive T cells, enter the bloodstream and migrate to secondary lymphoid organs such as lymph nodes and spleen, where they initiate peripheral maturation. These RTEs represent the youngest cohort of peripheral T cells and exhibit distinct phenotypic markers, including high expression of CD31 (PECAM-1), which distinguishes them from more mature naive T cells that lose this marker over time. This post-thymic phase allows RTEs to integrate into the peripheral pool while maintaining a quiescent state, ensuring a continuous supply of antigen-inexperienced T cells to support immune surveillance.^[36]^[37]^[38] The survival of naive T cells in the periphery relies on tonic signals from interleukin-7 (IL-7) and low-affinity interactions with self-antigens presented by major histocompatibility complex (MHC) molecules, without triggering full activation. IL-7 binds to the IL-7 receptor, composed of the IL-7Rα (CD127) chain and the common gamma chain (γc), activating Janus kinases (JAK1 and JAK3) to promote anti-apoptotic proteins like Bcl-2, thereby sustaining quiescence and longevity. Concurrently, periodic contact with self-peptide-MHC complexes delivers weak T cell receptor (TCR) signals that reinforce survival pathways, such as those involving FoxO1 transcription factors, independent of co-stimulation. These mechanisms collectively prevent attrition and maintain the naive T cell compartment in steady-state conditions.^[39]^[40]^[41]^[42] In lymphopenic environments, such as those following infection, irradiation, or congenital immunodeficiency, naive T cells undergo homeostatic proliferation to restore and maintain population numbers. This process involves slow, antigen-independent divisions driven by IL-7 availability and self-MHC recognition, generating daughter cells that retain a naive phenotype while filling the depleted niche. Unlike rapid antigen-driven expansion, homeostatic proliferation is controlled and limited by resource competition, preventing exhaustion and ensuring balanced replenishment. Studies in lymphopenic mouse models demonstrate that this mechanism is essential for immune reconstitution, with human analogs observed in post-chemotherapy settings.^[43]^[44]^[45] Naive T cells exhibit a lifespan spanning months to years in humans, with average half-lives of approximately 4.2 years for CD4+ naive cells and 6.5 years for CD8+ naive cells, influenced by telomere attrition and metabolic quiescence.^[46] Telomere shortening occurs progressively due to episodic homeostatic divisions, limiting replicative potential and contributing to age-related declines in naive T cell diversity. Metabolically, these cells rely on oxidative phosphorylation in a low-energy state, supported by IL-7, which helps preserve longevity until antigen encounter. Factors like age and environmental stressors modulate this duration, with older individuals showing extended individual cell lifespans but reduced overall output.^[47]^[48]^[49]^[50]

Types and Subsets

Conventional αβ T Cells

Conventional αβ T cells represent the predominant subset of T lymphocytes in the adaptive immune system, comprising approximately 95% of T cells in human peripheral blood.^[51] These cells are characterized by their expression of a T cell receptor (TCR) composed of α and β chains, which form a disulfide-linked heterodimer associated with the CD3 complex for signal transduction. The variable regions of the αβ TCR specifically recognize peptide antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells, enabling antigen-specific immune responses. Naive conventional αβ T cells, which emerge from thymic development through TCR gene rearrangement, circulate through secondary lymphoid organs awaiting antigen encounter.^[2] Upon activation by antigen and co-stimulatory signals, these naive cells proliferate and differentiate into effector T cells, with the resulting subsets determined by the cytokine milieu; for instance, interleukin-12 (IL-12) promotes differentiation into T helper 1 (Th1) cells.^[52] A portion of activated cells also develops into memory T cells, providing long-term immunity through rapid recall responses upon re-exposure to the same antigen.^[2] Memory conventional αβ T cells are heterogeneous, with central memory T cells (T_CM) expressing CCR7 and homing to lymph nodes for secondary activation, while effector memory T cells (T_EM) lack CCR7 and reside primarily in peripheral tissues for immediate effector functions. This distinction allows for coordinated surveillance and response across lymphoid and non-lymphoid sites, enhancing the efficiency of adaptive immunity.^[53]

Innate-Like T Cells

Innate-like T cells represent a diverse group of non-conventional T lymphocytes that exhibit rapid, innate immune-like responses despite expressing T cell receptors (TCRs), distinguishing them from conventional αβ T cells through limited TCR diversity and recognition of non-peptide antigens presented by non-classical MHC-like molecules. These cells are enriched in barrier tissues and play key roles in early defense against infections, tissue surveillance, and immunoregulation. Major subsets include γδ T cells, natural killer T (NKT) cells, and mucosal-associated invariant T (MAIT) cells, each with unique TCR compositions and antigen specificities.^[54]^[55] γδ T cells express heterodimeric γδ TCRs and constitute approximately 1–5% of circulating T cells in humans, though they comprise higher proportions in mucosal and epithelial tissues, such as 10–30% in skin and up to 40% in intestinal intraepithelial lymphocytes. Unlike conventional T cells, they recognize non-peptide antigens, including phosphoantigens derived from microbial metabolism or host stress pathways, in a manner independent of classical MHC molecules, enabling broad reactivity to infected or transformed cells. These cells are particularly enriched in epithelia of the skin, gut, lungs, and reproductive tract, where they provide frontline immunosurveillance.^[56] NKT cells, a subset of αβ T cells with innate properties, are defined by their semi-invariant TCRs—Vα14-Jα18 in mice and Vα24-Jα18 in humans—paired with diverse β chains, and they recognize glycolipid antigens presented by the MHC class I-like molecule CD1d. They represent 0.1–1% of T cells in peripheral blood but are enriched in tissues like the liver (approximately 0.05–1% of hepatic lymphocytes), spleen, lungs, and adipose tissue. Upon activation, NKT cells rapidly produce cytokines such as IFN-γ, IL-4, and IL-17 within hours, mimicking innate lymphoid cell responses and bridging early immunity to adaptive phases.^[57] MAIT cells also utilize semi-invariant αβ TCRs, specifically Vα7.2-Jα33 in humans paired with limited Vβ chains, to recognize microbial riboflavin biosynthesis intermediates presented by the MHC-related protein MR1. They account for 1–10% of T cells in human blood and are highly abundant in mucosal sites, comprising up to 50% of T cells in the liver and significant populations in the gut and lungs, where they patrol against bacterial pathogens. This tissue residency supports their role in rapid antimicrobial responses at barrier interfaces.^[58]^[59] Developmentally, innate-like T cells originate primarily from thymic progenitors but follow distinct pathways that often bypass conventional double-positive thymocyte selection. γδ T cells arise from double-negative thymic precursors, rearranging γδ TCR genes early and exiting the thymus without progressing through the MHC-dependent double-positive stage, though some intestinal intraepithelial γδ subsets undergo extrathymic maturation influenced by local microbiota and cytokines like IL-7. NKT and MAIT cells develop through agonist selection in the thymus, where strong TCR signals from lipid or metabolite antigens on CD1d or MR1, respectively, induce expression of the transcription factor PLZF, promoting an effector-ready phenotype; post-thymically, many NKT cells mature further in the liver under IL-15 influence, while MAIT cells require gut microbiota for full expansion and functionality in intestinal and hepatic niches. These origins enable their pre-programmed, rapid responsiveness without prior antigen exposure.^[56]^[55]^[57]

Activation and Signaling

Antigen Recognition

T cells recognize foreign antigens through specific interactions between their T cell receptors (TCRs) and peptide-major histocompatibility complex (MHC) complexes displayed on the surface of other cells. This process is fundamental to distinguishing self from non-self and initiating adaptive immune responses. The TCR, composed of α and β chains in conventional T cells, binds to short peptide fragments (typically 8–25 amino acids) that are loaded into the peptide-binding groove of MHC molecules.^[60] MHC class II molecules present antigens derived from extracellular pathogens to CD4+ T cells, with these MHC II-peptide complexes primarily expressed on professional antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. In contrast, MHC class I molecules display peptides from intracellular sources, like viral proteins or tumor antigens, to CD8+ T cells and are expressed on virtually all nucleated cells. This division ensures that helper T cells (CD4+) coordinate responses to extracellular threats, while cytotoxic T cells (CD8+) target infected or abnormal cells.^[61] The docking of the TCR onto the MHC-peptide complex occurs in a conserved diagonal orientation, primarily mediated by the six complementarity-determining regions (CDRs) in the TCR variable domains. CDR1 and CDR2 loops contact the α-helices of the MHC molecule, providing specificity for MHC restriction, whereas the hypervariable CDR3 loops interact directly with the antigenic peptide, conferring peptide specificity. This structural arrangement allows TCRs to achieve both MHC restriction and peptide discrimination with relatively low affinity interactions.^[62] A specialized mechanism known as cross-presentation enables dendritic cells to load exogenous (extracellular) antigens onto MHC class I molecules, thereby priming CD8+ T cells against pathogens or tumors that do not directly infect APCs. This process involves routing MHC class I through endolysosomal compartments where exogenous peptides are acquired, facilitated by a tyrosine-based targeting signal in the MHC I cytoplasmic domain. Defects in this signal impair cross-presentation and antiviral CD8+ T cell responses.^[63] The sensitivity of T cell antigen recognition is enhanced by the serial triggering model, in which a single peptide-MHC complex can sequentially engage and trigger up to approximately 200 TCRs due to the rapid on-off kinetics of the interaction. This brief, successive binding amplifies signaling without requiring sustained TCR occupancy, allowing effective T cell activation even at low antigen densities on APCs.^[64]

Co-Stimulatory and Inhibitory Signals

T cell activation follows the two-signal model, where the first signal is provided by antigen recognition through the T cell receptor (TCR), and the second signal arises from co-stimulatory interactions between T cells and antigen-presenting cells (APCs) to ensure a productive immune response. Without co-stimulation, TCR engagement alone induces T cell anergy or tolerance, preventing inappropriate activation against self-antigens or harmless stimuli.^[65] The primary co-stimulatory pathway involves CD28 on T cells binding to B7-1 (CD80) or B7-2 (CD86) ligands on APCs, delivering the essential second signal that promotes T cell proliferation, survival, and cytokine production, particularly interleukin-2 (IL-2). This interaction enhances the expression of survival factors like Bcl-xL and drives metabolic reprogramming to support effector functions. Inhibitory signals counterbalance activation to maintain immune homeostasis and prevent autoimmunity. CTLA-4, a CD28 homolog expressed on activated T cells, competes with CD28 for B7 ligands with higher affinity, thereby dampening T cell responses by sequestering co-stimulatory molecules and actively inhibiting signaling. Similarly, PD-1 on T cells engages PD-L1 or PD-L2 on APCs and target cells, recruiting Src homology 2 domain-containing phosphatases (SHP-1 and SHP-2) to dephosphorylate key signaling molecules and suppress activation.^[66] Additional co-stimulatory molecules fine-tune T cell responses in specific contexts. ICOS, induced on activated T cells, interacts with ICOS ligand on APCs and B cells to promote differentiation of T follicular helper (Tfh) cells, enabling germinal center formation and antibody class switching. 4-1BB (CD137), a TNF receptor family member, provides survival signals to CD8+ effector T cells upon ligation by 4-1BB ligand, enhancing persistence and cytokine secretion without relying on CD28.^[67]

Intracellular Signaling Pathways

Upon engagement of the T cell receptor (TCR) with peptide-MHC complexes, proximal signaling initiates through the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within the CD3 complex, particularly the ζ-chain, by the Src family kinase Lck. Lck, anchored to the coreceptors CD4 or CD8, becomes activated via dephosphorylation at its inhibitory tyrosine residue (Y505) by CD45 phosphatase, allowing autophosphorylation at Y394 and subsequent ITAM targeting.^[12] This phosphorylation creates docking sites for the ζ-chain-associated protein kinase 70 (ZAP-70), which binds via its SH2 domains, gets phosphorylated by Lck, and initiates downstream signal amplification by phosphorylating adaptor proteins like LAT and SLP-76.^[68] Downstream of ZAP-70, phospholipase Cγ1 (PLCγ1) is recruited and activated, hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from endoplasmic reticulum stores, leading to store-operated calcium entry via CRAC channels and sustained cytosolic calcium elevation. This calcium flux activates calcineurin, a phosphatase that dephosphorylates nuclear factor of activated T cells (NFAT), enabling its nuclear translocation and cooperation with nuclear factor κB (NF-κB) and activator protein 1 (AP-1) to drive transcription of genes like IL-2. Meanwhile, DAG activates protein kinase Cθ (PKCθ), which promotes NF-κB activation through the IKK complex, and recruits RasGRP1 to initiate further cascades.^[12]^[69] The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, activated via RasGRP1-Ras-Raf-MEK signaling, promotes T cell proliferation and differentiation by phosphorylating transcription factors such as Elk-1. Complementarily, the phosphoinositide 3-kinase (PI3K)-Akt pathway is engaged through co-stimulatory signals, where PI3K generates PIP3 to recruit and activate Akt, supporting cell survival, metabolic reprogramming toward glycolysis, and inhibition of pro-apoptotic proteins like FoxO.^[12]^[70] To prevent excessive activation, negative feedback mechanisms attenuate these pathways. The phosphatase and tensin homolog (PTEN) dephosphorylates PIP3, thereby limiting PI3K-Akt signaling duration and maintaining T cell homeostasis. Suppressor of cytokine signaling (SOCS) proteins, induced post-activation, inhibit Janus kinase (JAK)-STAT pathways and indirectly dampen TCR signals by targeting upstream kinases for degradation.^[12]^[71]

Functions

Helper and Regulatory Roles

CD4+ T helper cells play a central role in orchestrating adaptive immune responses by differentiating into specialized subsets that secrete distinct cytokine profiles to coordinate immunity against diverse pathogens.^[72] Upon activation through antigen recognition and co-stimulatory signals, these cells amplify innate responses, promote B cell antibody production, and regulate inflammation.^[73] Th1 cells are characterized by their production of interferon-gamma (IFN-γ), which activates macrophages to enhance their phagocytic and microbicidal activities against intracellular pathogens such as Mycobacterium tuberculosis.^[72] This cytokine also promotes the differentiation of cytotoxic T cells and stimulates dendritic cell maturation, thereby bridging innate and adaptive immunity.^[74] Th2 cells secrete interleukin-4 (IL-4), IL-5, and IL-13, which drive humoral immunity by inducing B cell class switching to IgE and IgG1 antibodies, as well as eosinophil activation and recruitment.^[73] These cytokines are pivotal in defense against helminth infections but also contribute to allergic disorders by promoting mast cell proliferation and mucus hypersecretion in the airways.^[73] Th17 cells produce IL-17 and IL-22, which recruit neutrophils to sites of infection and enhance epithelial barrier integrity, providing critical protection against extracellular bacteria and fungi like Candida albicans.^[75] IL-17 induces antimicrobial peptide production in epithelial cells, while IL-22 supports tissue repair during fungal infections; however, dysregulated Th17 responses are implicated in autoimmune conditions such as psoriasis and rheumatoid arthritis.^[76]^[77] Regulatory T cells (Tregs), defined by expression of the transcription factor FoxP3, maintain immune homeostasis by suppressing excessive responses through secretion of IL-10 and transforming growth factor-β (TGF-β).^[78] These cytokines inhibit effector T cell proliferation and dendritic cell activation, preventing autoimmunity and promoting tolerance to self-antigens and commensal microbes.^[79] Tregs also express CTLA-4 to compete with effector cells for co-stimulatory ligands, further dampening inflammation.^[80]

Cytotoxic and Effector Roles

Cytotoxic T cells, primarily CD8+ effector T cells, play a critical role in eliminating virally infected cells and malignant tumors through direct contact-dependent mechanisms. Upon recognition of peptide-MHC class I complexes on target cells, these T cells deploy lytic granules and death ligands to induce apoptosis, ensuring precise destruction without widespread tissue damage. This effector function is essential for immune surveillance and control of intracellular pathogens.^[81] The perforin-granzyme pathway represents the primary mechanism of cytotoxicity in CD8+ T cells. Perforin, a calcium-dependent pore-forming protein released from cytotoxic granules, oligomerizes in the target cell's plasma membrane to create 5–20 nm pores, allowing entry of granzymes such as granzyme B. Once inside the cytosol, granzyme B cleaves Bid to generate truncated Bid (tBid), which translocates to mitochondria, releasing cytochrome c and forming the apoptosome; this activates initiator caspase-9 and effector caspases-3 and -7, culminating in apoptotic DNA fragmentation and cell death. Granzyme B also directly activates caspase-3 and cleaves intracellular substrates like inhibitor of caspase-activated DNase (ICAD), amplifying the apoptotic signal.^[82] In parallel, CD8+ T cells utilize the Fas-Fas ligand (FasL) interaction for target cell elimination. FasL, expressed on the surface of activated cytotoxic T cells, binds to Fas (CD95) receptors on target cells, recruiting Fas-associated death domain (FADD) protein. This trimerizes Fas and activates caspase-8 via the death-inducing signaling complex (DISC), initiating a caspase cascade that leads to apoptosis through cleavage of cellular proteins and DNA damage. This extrinsic pathway complements granule exocytosis and is particularly effective against Fas-expressing infected or tumor cells.^[81] Beyond direct lysis, cytotoxic T cells secrete cytokines that amplify their effector roles. Tumor necrosis factor-alpha (TNF-α), produced by CD8+ T cells, promotes inflammation by recruiting additional immune cells and inducing apoptosis in susceptible targets via TNFR1 signaling, which activates caspases and NF-κB pathways. Interferon-gamma (IFN-γ), another key cytokine from these cells, establishes an antiviral state in neighboring cells by upregulating MHC class I expression and inhibiting viral replication through JAK-STAT signaling, while also enhancing macrophage activation for broader antimicrobial effects. These cytokines are regulated by transcription factors like T-bet and Eomesodermin in CD8+ T cells.^[83] Serial killing enables a single cytotoxic T cell to eliminate multiple targets efficiently. Formation of the immunological synapse—a structured adhesion and signaling interface at the T cell-target contact site—facilitates polarized release of cytotoxic granules toward the bound cell. After inducing death in one target, the T cell disengages, replenishes its granules, and rapidly forms new synapses with adjacent targets, allowing sequential engagements without prolonged commitment to a single cell. This dynamic process is crucial for clearing high-density infections or tumors.^[84]

Clinical Relevance

Immunodeficiencies

Immunodeficiencies involving T cells arise from genetic or acquired defects that impair T cell development, maturation, or function, resulting in profound susceptibility to viral, fungal, and opportunistic infections due to inadequate cellular immunity. These disorders often manifest early in life with recurrent or severe infections, failure to thrive, and increased mortality if untreated, highlighting the critical role of T cells in host defense.^[85] Severe Combined Immunodeficiency (SCID) represents the most severe form of T cell deficiency, characterized by mutations that abolish adaptive immunity. Common genetic causes include null mutations in the recombination-activating genes RAG1 or RAG2, which disrupt V(D)J recombination essential for T cell receptor (TCR) and B cell receptor assembly, leading to the absence of mature T and B cells while natural killer (NK) cells may be preserved.^[86] Another prevalent etiology is mutations in the interleukin-2 receptor gamma chain gene (IL2RG), responsible for X-linked SCID, which impairs cytokine signaling and results in the depletion of T, B, and NK cells, rendering patients highly vulnerable to infections from birth.^[87] Without interventions like hematopoietic stem cell transplantation, SCID is fatal within the first year of life due to overwhelming infections.^[88] DiGeorge syndrome, also known as 22q11.2 deletion syndrome, stems from a microdeletion on chromosome 22q11.2 that affects multiple genes, including TBX1, leading to thymic hypoplasia or aplasia and consequently reduced T cell production. This partial T cell deficiency varies in severity but commonly presents with low naive T cell counts, recurrent infections, and hypocalcemia due to parathyroid involvement.^[89] The thymic defect limits positive and negative selection of T cells, as briefly referenced in thymic development processes, contributing to immune dysregulation beyond mere cell number reduction.^[90] Acquired CD4+ T cell lymphocytopenia exemplifies functional T cell impairment, most notably in human immunodeficiency virus (HIV) infection, where the virus preferentially targets and depletes CD4+ T cells through direct cytopathic effects and immune-mediated destruction. This progressive loss, often dropping below 200 cells/μL, predisposes individuals to opportunistic infections such as Pneumocystis jirovecii pneumonia, cryptococcal meningitis, and cytomegalovirus retinitis.^[91] Unlike primary genetic defects, HIV-related depletion is reversible with antiretroviral therapy, which restores CD4+ counts and immune competence.^[92] Diagnosis of T cell immunodeficiencies relies on laboratory assessments to quantify and characterize T cell populations and function. Flow cytometry is the cornerstone for enumerating CD4+ and CD8+ T cell subsets, identifying lymphopenia or imbalances that suggest SCID (e.g., <300 CD3+ T cells/μL) or partial defects like DiGeorge syndrome.^[85] Functional evaluation through mitogen proliferation assays, such as phytohemagglutinin (PHA) stimulation, measures T cell responsiveness; absent or markedly reduced proliferation (<10% of normal) confirms severe dysfunction in SCID or similar disorders.^[93] These tests, combined with genetic sequencing, enable precise classification and guide therapeutic decisions.^[88]

Autoimmunity and Tolerance

T cell tolerance is established through central and peripheral mechanisms to prevent autoimmunity, but failures in these processes can lead to the escape of self-reactive T cells and subsequent autoimmune diseases. In the thymus, central tolerance primarily occurs via negative selection, where developing T cells with high-affinity recognition of self-antigens presented by thymic epithelial cells are deleted. The autoimmune regulator (AIRE) protein plays a critical role in this process by promoting the ectopic expression of peripheral tissue antigens in medullary thymic epithelial cells, thereby enabling the deletion of self-reactive T cell clones. Defects in AIRE, as seen in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), result in the escape of autoreactive T cells from the thymus, leading to multi-organ autoimmunity.^[94]^[95] Peripheral tolerance mechanisms serve as a secondary safeguard, maintaining immune homeostasis outside the thymus by rendering escaped self-reactive T cells unresponsive or eliminating them. These include clonal anergy, where T cells encountering self-antigens without sufficient co-stimulation become functionally inert; activation-induced cell death, leading to deletion of autoreactive cells; and suppression by regulatory T cells (Tregs), which inhibit effector T cell responses through cytokine secretion and cell-cell contact. Breakdown of peripheral tolerance contributes to diseases such as type 1 diabetes (T1D), where dysregulated Th1 and Th17 cells promote pancreatic beta-cell destruction. In T1D, Th1 cells drive pro-inflammatory interferon-gamma production, while Th17 cells amplify inflammation via interleukin-17, often due to imbalances in Treg suppression and effector T cell expansion.^[96]^[97]^[98]^[99]^[100] Molecular mimicry represents another pathway by which infections can trigger T cell-mediated autoimmunity, where microbial antigens structurally resemble self-peptides, leading to cross-reactive T cell responses against host tissues. A classic example is acute rheumatic fever following group A Streptococcus infection, in which T cells recognizing streptococcal M protein epitopes also target cardiac myosin, resulting in valvulitis and carditis. This cross-reactivity arises from shared amino acid sequences or conformational similarities, activating autoreactive T cells that escaped central or peripheral tolerance.^[101]^[102] Therapeutic strategies to restore T cell tolerance in autoimmunity often focus on modulating T cell activation to induce regulatory responses. Non-mitogenic anti-CD3 monoclonal antibodies, such as teplizumab, promote transient T cell activation followed by anergy or apoptosis of effector cells, while expanding Tregs to suppress ongoing autoimmunity. Clinical trials have demonstrated that low-dose anti-CD3 therapy delays progression in recent-onset T1D by inducing tolerance without broad immunosuppression, highlighting its potential in antigen-specific immune modulation.^[103]^[104]^[105] Emerging approaches include chimeric antigen receptor (CAR) T cell therapies targeting autoreactive B cells or plasma cells in autoimmune diseases. As of 2025, phase 1 and 2 clinical trials have shown promising results, including immune system reset and long-term remission in conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis, without the need for chronic immunosuppression. For instance, CD19-directed CAR-T therapies have demonstrated efficacy in depleting pathogenic B cells, with data from trials presented at the ACR Convergence 2025. In vivo CAR-T generation methods are also under investigation to improve accessibility.^[106]^[107]

Cancer Immunotherapy

T cells play a central role in cancer immunotherapy by recognizing and eliminating tumor cells through antigen-specific mechanisms. Tumor antigens, particularly neoantigens arising from somatic mutations in cancer cells, are processed and presented on major histocompatibility complex class I (MHC I) molecules, enabling recognition by cytotoxic CD8+ T cells. These neoantigens are unique to the tumor and provoke strong T cell responses, distinguishing malignant cells from healthy tissue and forming the basis for personalized immunotherapies.^[108] Checkpoint inhibitors represent a cornerstone of T cell-based cancer therapy by blocking inhibitory signals that tumors exploit to evade immune detection. Ipilimumab, an anti-CTLA-4 monoclonal antibody, was the first such agent approved by the FDA in 2011 for unresectable or metastatic melanoma, based on phase 3 trials demonstrating improved overall survival compared to vaccine alone. Similarly, pembrolizumab, an anti-PD-1 antibody, received accelerated FDA approval in 2014 for advanced melanoma, with subsequent expansions to other indications following trials showing durable responses in 20-40% of patients by reinvigorating exhausted T cells. These therapies enhance T cell activation and proliferation within the tumor microenvironment, leading to regression in immunogenic cancers like melanoma and non-small cell lung cancer.^[109]^[110] Chimeric antigen receptor (CAR) T cell therapy engineers patient-derived T cells to express synthetic receptors targeting tumor-specific antigens, bypassing MHC restriction for direct cytotoxicity. Tisagenlecleucel, a CD19-directed CAR-T product, was approved by the FDA in 2017 for relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in patients up to 25 years old, achieving complete remission rates of approximately 80% in pivotal trials. A common adverse effect, cytokine release syndrome (CRS), arises from massive T cell activation and cytokine release, manifesting as fever, hypotension, and organ dysfunction; management involves supportive care, tocilizumab (an IL-6 receptor antagonist), and corticosteroids for severe cases, with grading systems like ASTCT consensus guiding intervention. In June 2025, the FDA eliminated the Risk Evaluation and Mitigation Strategies (REMS) requirements for autologous CAR-T therapies, streamlining administration while maintaining vigilant monitoring for adverse events like CRS. While highly effective for hematologic malignancies, CAR-T challenges in solid tumors include antigen heterogeneity and immunosuppressive environments.^[111]^[112]^[113] Tumor-infiltrating lymphocyte (TIL) therapy harnesses naturally occurring T cells isolated from patient tumors, expanded ex vivo, and reinfused to target solid tumors. Lifileucel, an autologous TIL product, received FDA accelerated approval in 2024 for advanced melanoma previously treated with checkpoint inhibitors and targeted therapies, with objective response rates of 31% in phase 2 trials including durable complete responses in some patients. T cell receptor (TCR)-engineered therapies represent another advancement; afamitresgene autoleucel, a TCR-T targeting MAGE-A4, was approved in 2024 for synovial sarcoma, offering MHC-restricted recognition for solid tumors. Recent advances as of 2025 incorporate bispecific antibodies, such as T-cell engagers that simultaneously bind tumor antigens (e.g., HER2 or EGFR) and CD3 on T cells, enhancing recruitment and activation at the tumor site without prior MHC presentation. These bispecifics, including linvoseltamab-gcpt approved in July 2025 for relapsed/refractory multiple myeloma, improve T cell infiltration and effector function, addressing limitations of TIL persistence and showing promise in combination regimens for broader efficacy.^[114]^[115]^[116]^[117]

T Cell Exhaustion

T cell exhaustion refers to a state of progressive dysfunction in T cells, particularly CD8+ T cells, induced by persistent antigen stimulation during chronic infections or cancer, leading to diminished proliferative capacity, cytokine production, and cytotoxic potential. This hyporesponsive state is distinct from anergy or senescence, as exhausted T cells remain viable but exhibit a unique transcriptional and epigenetic program that sustains their impaired function. The phenomenon was first characterized in the murine model of chronic lymphocytic choriomeningitis virus (LCMV) infection, where virus-specific CD8+ T cells fail to clear the pathogen despite initial activation.^[118] At the molecular level, T cell exhaustion is driven by epigenetic modifications that lock in a dysfunctional gene expression profile. Sustained expression of the transcription factor TOX (thymocyte selection-associated high mobility group box) is a central regulator, induced by prolonged calcium signaling through NFAT during chronic antigen exposure. TOX binds to chromatin and promotes accessibility at exhaustion-associated loci while repressing effector genes, thereby enforcing the exhausted phenotype in a heritable manner. In TOX-deficient mice, CD8+ T cells resist exhaustion during chronic LCMV infection, maintaining effector functions and contributing to viral control. Exhausted T cells progressively upregulate multiple inhibitory receptors, including PD-1, TIM-3, and LAG-3, which collectively suppress T cell activation and effector responses. These receptors form a co-inhibitory network; for instance, PD-1 engagement inhibits downstream signaling via SHP-1/2 phosphatases, while TIM-3 and LAG-3 further dampen cytokine secretion and proliferation. This upregulation correlates with a profound loss of cytokine production, such as reduced IFN-γ and TNF-α, rendering T cells unable to mount effective responses. In the LCMV model, sequential expression of these markers delineates stages of exhaustion, from progenitor-like cells with intermediate PD-1 to terminally exhausted cells co-expressing all three.^[118] Metabolically, exhausted T cells undergo a shift from aerobic glycolysis, characteristic of effector T cells, to reliance on oxidative phosphorylation and fatty acid oxidation for energy maintenance. This adaptation supports survival in antigen-rich environments but impairs rapid proliferation and effector functions due to mitochondrial dysfunction and reduced glycolytic flux. In chronic LCMV infection, exhausted CD8+ T cells exhibit bioenergetic insufficiencies, including lower spare respiratory capacity, which limits their responsiveness even upon receptor blockade.^[119] In chronic viral infections like HIV and hepatitis C virus (HCV), T cell exhaustion manifests similarly, with virus-specific CD8+ T cells showing high PD-1 expression and impaired cytokine production, contributing to persistent viremia. In HIV, exhausted T cells correlate with disease progression, while in HCV, exhaustion hinders viral clearance but can be partially reversed. PD-1 blockade in these settings restores some T cell functions, such as proliferation and cytokine secretion, though full recovery is limited by epigenetic barriers like TOX-mediated changes.^[120] As of 2025, therapeutic strategies to overcome T cell exhaustion include next-generation CAR-T designs with metabolic modulators to enhance persistence, gene editing to disrupt exhaustion pathways like TOX, and drug-loaded bispecific T cell engagers that mitigate exhaustion during chronic stimulation. These approaches aim to reinvigorate T cells in immunotherapy-resistant tumors and infections.^[121]^[122]

References

[1]
Introduction to T and B lymphocytes - Autoimmunity - NCBI Bookshelf
They stimulate strong cell immunity to intracellular pathogens as well as participate in the pathogenesis of the autoinmune diseases and in the development of ...Introduction · T-lymphocytes (T cells) · lymphocytes (B cells)
[2]
T cells in health and disease | Signal Transduction and Targeted ...
Jun 19, 2023 · T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus.
[3]
T Cell-Mediated Immunity - Immunobiology - NCBI Bookshelf - NIH
Effector T cells, as we learned in Chapter 5, fall into three functional classes that detect peptide antigens derived from different types of pathogen.
[4]
Different Subsets of T Cells, Memory, Effector Functions, and CAR-T ...
Mar 15, 2016 · This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy.1. Introduction · 2. Cd4 Cell Subsets · 4. Cd8 Cell Subsets And Cell...
[5]
Human T cell development, localization, and function throughout life
Feb 20, 2019 · T cells coordinate multiple aspects of adaptive immunity throughout life, including responses to pathogens, allergens, and tumors.
[6]
Rapid Quantification of Mitogen-induced Blastogenesis in T ...
Dec 27, 2016 · The cell diameter data collected from resting and activated T cells after 48 hr of PMA/ionomycin stimulation are summarized in Table 1. The ...
[7]
Mini-review Mitochondrial activity in T cells - ScienceDirect.com
Naïve T cells are metabolically quiescent, with minimal nutrient uptake, and they make efficient use of mitochondrial processes to produce ATP, tending to ...Missing: few | Show results with:few
[8]
Activation effects on the physical characteristics of T lymphocytes
May 15, 2023 · The cell volume increased substantially upon cell activation from ∼200 μm3 to ∼650 μm3. Naive and activated T cells had similar mean cortical ...Missing: diameter | Show results with:diameter
[9]
Pathways for Cytokine Secretion | Physiology
Aug 1, 2010 · Constitutive cytokine release describes the packaging of cytokines through the ER and Golgi into a continuously trafficking pathway of carrier ...Cytokine Secretion And... · Macrophages · Polarity Of Cytokine Release
[10]
Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration ...
Centrosome-associated organelles, such as the Golgi apparatus, endosomes, or lytic granules, move together with microtubules toward the contact site. Actin ...
[11]
Membrane Ultrastructure and T Cell Activation - Frontiers
In this review, we provide an overview of the common microscopy techniques used to image T cells (see Box 1) and discuss the types of membrane structures ...
[12]
T cell receptor (TCR) signaling in health and disease - Nature
Dec 13, 2021 · Components and structure of TCR complex. The core TCR complex consists of two TCR chains and six cluster of differentiation 3 (CD3) chains. ...
[13]
TCP - Overview: T-Cell Subsets, Naive, Memory, and Activated, Blood
T cells can be subdivided into naive and memory subsets based on the expression of cell-surface markers, such as CD45RA and CD45RO among others. It was ...
[14]
The structural basis of T-cell receptor (TCR) activation: An enduring ...
The T-cell receptor (TCR)–CD3 complex is composed of a diverse αβ TCR heterodimer noncovalently associated with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ ...
[15]
Structural and Biophysical Insights into the Role of CD4 ... - Frontiers
CD4 and CD8 enhance T cell signaling by binding MHC class II (CD4) or MHC class I (CD8) molecules on APCs. The interaction of CD4 with MHC class II greatly ...
[16]
CD4 and CD8 binding to MHC molecules primarily acts to enhance ...
It is generally thought that the ability of these coreceptors to enhance T-cell responses is due to two main effects: (i) Binding of CD4 and CD8 to MHC class II ...Missing: sources | Show results with:sources
[17]
CD45 isoforms in T cell signalling and development - ScienceDirect
The CD45 phosphotyrosine phosphatase is expressed on T cells as multiple isoforms due to alternative splicing. The panoply of isoforms expressed is tightly ...
[18]
CD28 costimulation: from mechanism to therapy - PMC
Summary. Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation.Missing: seminal | Show results with:seminal
[19]
LFA-1 in T cell priming, differentiation, and effector functions - PMC
The integrin LFA-1 is crucial for T cell entry into mammalian lymph nodes and tissues, and for promoting interactions with antigen-presenting cells.
[20]
Prolonged Interleukin-2Rα Expression on Virus-Specific CD8+ T ...
Jan 29, 2010 · CD25, the high-affinity interleukin-2 (IL-2) receptor α chain, is rapidly upregulated by antigen-specific CD8+ T cells after T cell receptor ...
[21]
T-Cell Lineage Determination - PMC - NIH
T cells originate from hematopoietic stem cells (HSCs) in the bone marrow but complete their development in the thymus. HSCs give rise to a variety of non- ...
[22]
Thymus-autonomous T cell development in the absence of ...
Jul 9, 2012 · The most immature T cell progenitors in the normal thymus are early thymic progenitors (ETP; CD44+CD25−Kit+ within the CD3− DN1 ...
[23]
Finding their niche: chemokines directing cell migration in the thymus
Dec 7, 2010 · Collectively, evidence suggests that CCR7/CCL21/CCL19 and CCR9/CCL25 are the two main chemokine axes required for precursor entry into the ...
[24]
Maintenance of a normal thymic microenvironment and T-cell ...
Nov 1, 2008 · The thymus provides a specialized environment adept to attract lymphoid precursor cells and to control their survival, expansion, ...
[25]
Deconstructing the Thymic Microenvironment Through Genesis to ...
Jun 25, 2025 · The thymus is essential for adaptive immunity, orchestrating the differentiation of hematopoietic progenitors into various T‐cell lineages.
[26]
Mesenchymal cells are required for functional development of ...
Epithelial–mesenchymal interactions have essential roles in thymus organogenesis. Mesenchymal cells are known to be required for epithelial cell proliferation.Mesenchymal Cells Are... · Co-Culture Of Thymus Anlagen... · Results
[27]
RAG-1 and RAG-2, Adjacent Genes That Synergistically Activate V ...
RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction.
[28]
Mechanics of T cell receptor gene rearrangement - PMC - NIH
TCR genes are assembled through V(D)J recombination, a site specific recombination process directed by the lymphoid-specific recombinase (RAG, composed of RAG1 ...
[29]
Regulation of thymocyte differentiation: pre-TCR signals and beta ...
Signals derived from the pre-TCR complex trigger a maturation program within developing thymocytes that includes: rescue from apoptosis; inhibition of further ...
[30]
V(D)J Recombination: Recent Insights in Formation of the ... - Frontiers
Apr 28, 2022 · V(D)J recombination is an essential mechanism of the adaptive immune system, producing a diverse set of antigen receptors in developing lymphocytes.Abstract · Introduction · Concluding Remarks and...
[31]
Unraveling V(D)J Recombination: Insights into Gene Regulation
The discovery of RAG-1 and RAG-2 has been the most important advance in the study of V(D)J recombination since the original discovery of gene rearrangement ...
[32]
Mice Lacking TdT: Mature Animals with an Immature Lymphocyte ...
Receptor genes from adult mice carrying a mutation in the terminal deoxynucleotidyl transferase (TdT) gene have few N nucleotides, providing proof that this ...
[33]
Most α/β T Cell Receptor Diversity Is Due to Terminal ...
Tdt adds nucleotides at 3′ ends of each coding gene segment (6). Each TCR junction bears 2 to 3 nucleotides on the average (for a review, see reference 7). In ...
[34]
Positive and negative selection of the T cell repertoire
Intriguingly, cortical negative selection of thymocytes specific for 'ubiquitous' self-antigens was shown to depend on a crucial contribution of dendritic cells ...
[35]
Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic ...
Apr 19, 1974 · Doherty, P. C., Zinkernagel, R. M., and Ramshaw, I. A., J. Immun ... Nature 248, 701–702 (1974). https://doi.org/10.1038/248701a0.Missing: MHC | Show results with:MHC
[36]
Life after the thymus: CD31+ and CD31− human naive CD4+ T-cell ...
Jan 22, 2009 · RTEs are naive peripheral T cells, which have only recently exited the thymus and have not undergone further peripheral proliferation and ...
[37]
Recent thymic emigrants and mature naïve T cells exhibit differential ...
Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery, and exhibit phenotypic and functional characteristics distinct from those of ...
[38]
Correlation between recent thymic emigrants and CD31 + (PECAM ...
Oct 24, 2007 · Sorted CD31+CD45RA+RO– naive CD4+ lymphocytes contained high TREC numbers, whereas CD31+CD45RA–RO+ cells (comprising ⩽5% of CD4+ cells during ...
[39]
IL-7 is critical for homeostatic proliferation and survival of naïve T cells
In T cell-deficient conditions, naïve T cells undergo spontaneous “homeostatic” proliferation in response to contact with self-MHC/peptide ligands.
[40]
Homeostasis of Naive and Memory T Cells - ScienceDirect.com
Dec 19, 2008 · The survival signal induced by IL-7 binding is mediated through the activation of Jak1 and Jak3, which are bound to CD127 and γc, respectively ( ...
[41]
Self–class I MHC molecules support survival of naive CD8 T cells ...
We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, ...
[42]
Homeostasis of Naive and Memory T Cells: Immunity - Cell Press
Dec 19, 2008 · In the case of naive T cells, prolonged survival of these cells in interphase is dependent on a combination of covert TCR signaling from ...
[43]
Cytokine Requirements for Acute and Basal Homeostatic ...
For example, T lymphocytes are known to divide independently of cognate antigen in lymphopenic environments. This “acute homeostatic proliferation” is thought ...Introduction · Materials And Methods · Results And Discussion
[44]
The molecular program induced in T cells undergoing homeostatic ...
Nov 17, 2004 · This lymphopenia-induced homeostatic proliferation (HP) requires both T cell receptor (TCR)-transmitted and cytokine-mediated signals. When ...
[45]
Homeostatic Expansion of T Cells during Immune Insufficiency ...
In this study, we show that reduced T cell numbers and the resulting exaggerated homeostatic-type proliferation of T cells generate autoimmunity.
[46]
Life span of naive and memory T cells - PubMed - NIH
Studies on T cell turnover indicate that most peripheral T cells can remain in a resting state for long periods (months in rodents and years in humans).
[47]
Losing TREC with age - PMC - NIH
Earlier results from the same group indicated that human naïve CD4 T cells have an average half-life of six years whereas CD8 T cells have an average half-life ...
[48]
Age-associated remodeling of T cell immunity and metabolism - PMC
Telomere length is significantly reduced in the naïve CD8+ T cell compartment, likely as consequence of heightened homeostatic proliferation in aged hosts.
[49]
Review Age-associated remodeling of T cell immunity and metabolism
Jan 3, 2023 · Naive T cells exist in a state of quiescence characterized by low metabolic activity and preferential use of OXPHOS for the generation of ATP.
[50]
Human gamma-delta (γδ) T cell therapy for glioblastoma
Sep 1, 2023 · However, γδ T cells, as a small subset (1–5%) of T cells in human peripheral blood, are relatively unknown compared to conventional alpha-beta ( ...
[51]
TRBC1 - T cell receptor beta constant 1 - UniProt
Jul 18, 2018 · Alpha-beta TR is a heterodimer composed of an alpha and beta chain; disulfide-linked. The alpha-beta TR is associated with the transmembrane ...
[52]
IL-12 signaling drives the differentiation and function of a TH1 ...
Sep 30, 2019 · Naïve T helper cells differentiate into a number of effector subsets that coordinate pathogen-specific immune responses including T helper 1 (TH ...
[53]
Complex Memory T-Cell Phenotypes Revealed by Coexpression of ...
Antigen-experienced T cells have been divided into CD62L+ CCR7+ central memory (TCM) and CD62L− CCR7− effector memory (TEM) cells.
[54]
Developmental features and unique characteristics of peptide ...
Jun 6, 2025 · The innate-like T cell lineage encompasses a diverse group of αβ and γδ T cells that exhibit features of both adaptive and innate immunity.
[55]
γδ T cells: origin and fate, subsets, diseases and immunotherapy
Nov 22, 2023 · In this comprehensive review, we explore the origin and fate of γδ T cells, their subsets, their relevance to various diseases including infections, autoimmune ...<|control11|><|separator|>
[56]
Invariant natural killer T cells in lung diseases
Sep 11, 2023 · Unlike conventional T cells, NKT cells express TCRs that recognize glycolipid antigens loaded on CD1d, which is a nonpolymorphic major ...
[57]
MAIT cells specific for microbial metabolites - Nature
Oct 19, 2012 · The T cell receptor (TCR) of the innate-like mucosal-associated invariant T (MAIT) cells consists of an invariant Vα chain combined with ...<|separator|>
[58]
Single-cell analysis of human MAIT cell transcriptional, functional ...
Aug 14, 2023 · Overall, human MAIT cells show variation in phenotype, function and TCR repertoire. However, it is unknown whether they comprise multiple ...
[59]
Why must T cells be cross-reactive? | Nature Reviews Immunology
Aug 24, 2012 · By contrast, the CD4 and CD8 glycoproteins have a unique role in 'co-receiving' peptide–MHC molecules by binding to largely invariant sites on ...Abstract · Main · Author Information
[60]
The ABC of Major Histocompatibility Complexes and T Cell ...
In this review, we summarize the lessons learned over the last 45 years since the seminal discovery of MHC-restriction by Doherty and Zinkernagel, and outline ...
[61]
TCR docking | Nature Reviews Immunology
Sep 1, 2002 · The regions within the variable domains that comprise the peptide–MHC-binding interface are known as the complementarity-determining regions ( ...
[62]
Control of dendritic cell cross-presentation by the major ... - Nature
Oct 19, 2003 · Dendritic cells (DCs) can present extracellularly derived antigens in the context of major histocompatibility complex (MHC) class I molecules, a process called ...Missing: paper | Show results with:paper
[63]
Serial triggering of many T-cell receptors by a few peptide–MHC ...
May 11, 1995 · Here we show that a small number of peptide–MHC complexes can achieve a high TCR occupancy, because a single complex can serially engage and trigger up to ∼200 ...Missing: recognition | Show results with:recognition
[64]
The history of the two‐signal model of lymphocyte activation
The first ideas leading to The Two‐Signal Model of lymphocyte activation were published 50 years ago, but the model was not realized in one sitting.Missing: seminal | Show results with:seminal
[65]
Enhancement of antitumor immunity by CTLA-4 blockade - PubMed
These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
[66]
4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell ...
Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-γ production by CD8+ T cells ...
[67]
A Story of Kinases and Adaptors: The Role of Lck, ZAP-70 and LAT ...
Aug 24, 2023 · In this review, we will examine and discuss the roles of the tyrosine kinases Lck and ZAP70 and the membrane adaptor LAT in these cellular processes.
[68]
Calcium–NFAT transcriptional signalling in T cell activation and T ...
NFAT proteins promote T cell activation and limit the immune response. They are activated by calcium signals and are central to activation markers.Missing: PLCγ IP3 DAG
[69]
Diverse Roles of Akt in T cells - PMC - PubMed Central
Jan 28, 2021 · Akt kinases translate various external cues into intracellular signals that control cell survival, proliferation, metabolism and differentiation.
[70]
Dysregulation of SOCS-Mediated Negative Feedback of Cytokine ...
Feb 7, 2017 · Suppressor of cytokine signaling (SOCS) proteins are major negative feedback regulators of cytokine signaling mediated by the Janus kinase (JAK)- ...
[71]
TH1 and TH2 cells: different patterns of lymphokine secretion lead to ...
TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989:7:145-73. doi: ...
[72]
Two types of murine helper T cell clone. I. Definition ... - PubMed
TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse ...Missing: 1989 paper PDF
[73]
Molecular Mechanisms of T Helper Cell Differentiation and ... - NIH
Th1 cells produce IFN-γ, which stimulates macrophages and CTLs. Stimulated macrophages kill intracellular pathogens by activating microbicidal mechanisms ...
[74]
Interleukin 17-producing CD4+ effector T cells develop via a lineage ...
CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined.
[75]
IL-22 defines a novel immune pathway of antifungal resistance
May 5, 2010 · In this study, we provide evidence that IL-22, which is also produced by Th17 cells, has a critical, first-line defense in candidiasis.Missing: Contro | Show results with:Contro
[76]
IL-17/Th17 in anti-fungal immunity: what's new? - PubMed
Here we discuss how recent findings in experimental candidiasis and aspergillosis shed new lights on the contribution of Th17 cells to resistance and pathology ...Missing: 22 paper
[77]
Control of regulatory T cell development by the transcription factor ...
Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice,Missing: 2008 paper
[78]
Regulatory T cells – a brief history and perspective - Sakaguchi - 2007
Oct 31, 2007 · It is now widely accepted that the normal immune system harbors a regulatory T-cell population specialized for immune suppression.
[79]
How regulatory T cells work - PMC - PubMed Central - NIH
Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases.
[80]
Cytotoxic CD8 + T cells in cancer and cancer immunotherapy - Nature
Sep 15, 2020 · Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful ...
[81]
Intracellular versus extracellular granzyme B in immunity and disease
Sep 21, 2009 · The cytotoxic granzyme B (GrB)/perforin pathway has been traditionally viewed as a primary mechanism that is used by cytotoxic lymphocytes ...
[82]
CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential
Nov 1, 2023 · After infection, naïve CD8 T cells proliferate and differentiate into effector CD8 T cells, enabling them to efficiently eliminate infected ...
[83]
Understanding serial killers | Nature Immunology
Jun 20, 2023 · Cytotoxic T cells (CTLs) can rapidly kill multiple target cells ... cell, terminating TCR signaling and disengaging the CTL to enable serial ...
[84]
Flow Cytometry for Diagnosis of Primary Immune Deficiencies—A ...
This review focuses on use of flow cytometry in disease-specific diagnosis of PIDDs in the context of a developing country.
[85]
Severe Combined Immunodeficiency Disorder due to a Novel ... - NIH
Jan 7, 2021 · Null mutations cause severe combined immunodeficiency (SCID), with the absence of both B and T cells and preserved natural killer (NK) cells ...
[86]
Mutations in genes required for T-cell development: IL7R, CD45 ...
Mutations in any of eight known genes: IL2RG, ARTEMIS, RAG1, RAG2, ADA, CD45, JAK3, and IL7R cause SCID. Mutations in unidentified genes may also cause SCID.
[87]
The diagnosis of severe combined immunodeficiency (SCID) - NIH
Proliferative testing by mitogen stimulation with PHA, anti-CD3, or anti-CD3/CD28 antibodies may be performed, but may not be required to confirm the diagnosis ...Scid As A Pathophysiologic... · Suspected Scid · Typical Scid
[88]
DiGeorge Syndrome - StatPearls - NCBI Bookshelf
DGS results from microdeletion of 22q11.2, which encodes over 90 genes. Patients with DGS display a broad array of phenotypes, and the most common findings ...Introduction · History and Physical · Evaluation · Treatment / Management
[89]
T-cell lymphopenia in 22q11.2 deletion syndrome - NIH
Sep 28, 2017 · One of the most common features of 22q11.2del is T-cell lymphopenia due to thymic hypoplasia. T-cell lymphopenia is a risk factor for ...
[90]
CD4+ T cell depletion in HIV infection - PubMed Central - NIH
The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4 + T-cell populations in close association with ...
[91]
CD4 Cell Count and HIV - StatPearls - NCBI Bookshelf
The decline of CD4 T cells can lead to opportunistic infections and increase mortality. ... The Hitchhiker Guide to CD4(+) T-Cell Depletion in Lentiviral ...
[92]
Laboratory evaluation for T-cell dysfunction - PMC - NIH
Sep 9, 2014 · Additional flow cytometric studies that can be helpful in evaluating T-cell immunity include evaluation of naive versus memory T cells by using ...
[93]
Central tolerance to self revealed by the autoimmune regulator - PMC
It has become clear that Aire plays a key role in establishing T cell tolerance to self, particularly in the thymus.
[94]
The Many Faces of Aire in Central Tolerance - Frontiers
Oct 10, 2013 · An essential molecule in the induction of central tolerance is Autoimmune Regulator (Aire). The AIRE gene was identified by positional cloning ...
[95]
T-Cell Tolerance: Central and Peripheral - PMC
Cell types in central tolerance. (Top) T cells are positively selected in the thymic cortex. Negative selection via clonal deletion can also occur in the cortex ...
[96]
Immunological mechanisms of tolerance: Central, peripheral and the ...
Dec 11, 2023 · Tregs suppress the activity of both autoreactive T cells that escaped central deletion and T cells that cross-react with self-antigen as a ...
[97]
Molecular Mechanisms of Treg-Mediated T Cell ... - Frontiers
CD4+CD25highFoxp3+ regulatory T cells (Tregs) can suppress other immune cells and, thus, are critical mediators of peripheral self-tolerance.
[98]
Th17 Cells in Type 1 Diabetes: Role in the Pathogenesis and ...
A growing body of evidence supports an important role of T helper type 17 (Th17) cells along with impaired T regulatory (Treg) cells in the development of T1D.
[99]
Th17 cells in Type 1 diabetes: a future perspective - PMC - NIH
T1D is characterized as an autoimmune disease whereby CD4+ T cells are thought to mediate disease pathology. While the effector function of Th1 cells is ...
[100]
Rheumatic Fever, Autoimmunity and Molecular Mimicry - NIH
T cell clones from patients with rheumatic carditis respond to streptococcal M protein and cardiac myosin epitopes supporting the hypothesis that cardiac myosin ...
[101]
Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive ...
Cross-reactive antigens and antibodies were first found to be associated with acute rheumatic fever (ARF) and group A streptococci when it was discovered that ...
[102]
Induction of Immunological Tolerance by Oral Anti-CD3 - PMC
Several studies have demonstrated that oral (or nasal) administration of anti-CD3 monoclonal antibodies can be used to induce immune tolerance.
[103]
Therapeutic Anti-Cd3 Monoclonal Antibodies: From Bench to Bedside
Anti-CD3 monoclonal antibodies (mAbs) effectively treat autoimmune disease in animal models and have also shown promise in clinical trials.
[104]
Anti-CD3 therapy permits regulatory T cells to surmount T cell ...
Treatment with an antibody targeting CD3 is one of the more promising avenues currently being pursued for the therapy of organ-specific autoimmune diseases.
[105]
Neoantigens Generated by Individual Mutations and Their Role in ...
Nov 27, 2017 · An increasing number of studies have shown a strong association of the mutation/neoantigen burden with TIL infiltration and activity, as well as ...
[106]
Improved survival with ipilimumab in patients with metastatic ...
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic ...
[107]
Accelerated Approval of Pembrolizumab for Second-Line Treatment ...
Abstract. On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks.Missing: original | Show results with:original
[108]
FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for ...
Sep 7, 2017 · FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. On August 30, 2017, the U.S. Food and Drug ...Missing: axicabtagene ciloleucel
[109]
ASTCT Consensus Grading for Cytokine Release Syndrome and ...
The CARTOX CRS grading differs slightly from the Lee criteria by including grade 1 organ toxicity to be considered under grade 1 CRS and defining fever, ...
[110]
First Cancer TIL Therapy Gets FDA Approval for Advanced Melanoma
Mar 5, 2024 · FDA has approved lifileucel (Amtagvi), the first cancer treatment that uses immune cells called tumor-infiltrating lymphocytes, or TILs.
[111]
Bispecific T-cell engagers for the recruitment of T cells in solid tumors
BiTEs have the unique ability to crosslink T cells and tumor cells independently of major histocompatibility complex (MHC) restriction.
[112]
Molecular signature of CD8+ T cell exhaustion during chronic viral ...
Oct 18, 2007 · These data showed that exhausted CD8(+) T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and ...Missing: seminal paper
[113]
Long-term antigen exposure irreversibly modifies metabolic ... - eLife
Jun 18, 2018 · Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown.
[114]
Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand ...
Sep 25, 2006 · Recent work has shown that PD-1 is highly expressed on exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection in mice.<|separator|>