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Cytotoxic T cell

Cytotoxic T cells, also known as CD8+ T cells or cytotoxic T lymphocytes (CTLs), are a specialized subset of T lymphocytes that function as key effectors in the adaptive immune system, primarily responsible for recognizing and eliminating virus-infected cells, intracellular pathogens, tumor cells, and other abnormal cells through targeted induction of apoptosis.^[1] These cells originate from hematopoietic stem cells in the bone marrow and mature in the thymus, where they undergo positive and negative selection to ensure they can bind to major histocompatibility complex (MHC) class I molecules while avoiding self-reactivity.^[1] Upon maturation, naïve cytotoxic T cells circulate in the blood and lymphoid tissues until activation, after which they differentiate into effector cells capable of rapid cytotoxicity.^[1] Activation of cytotoxic T cells requires two signals: the first involves the T cell receptor (TCR) complex, including CD3 and CD8, recognizing antigenic peptides presented by MHC class I molecules on antigen-presenting cells or infected target cells, and the second is a costimulatory signal via CD28 binding to B7 molecules (CD80/CD86) on the presenting cell.^[2] This process forms an immunological synapse at the contact site, enabling polarized release of cytotoxic granules and preventing damage to bystander cells.^[3] Once activated, these cells proliferate and migrate to sites of infection or tumors, where they exert their effector functions.^[1] The primary mechanisms of cytotoxicity employed by these cells include the release of perforin and granzymes from lytic granules, as well as the expression of Fas ligand (FasL). Perforin polymerizes to form pores in the target cell membrane, allowing granzymes to enter and activate caspases, which dismantle the cell through apoptosis, a process that can occur within minutes of contact.^[3] Alternatively, FasL on the cytotoxic T cell binds to Fas receptors on the target, triggering an extrinsic apoptosis pathway via caspase-8 activation.^[3] In addition to direct killing, activated cytotoxic T cells secrete cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which enhance antiviral states in neighboring cells and activate other immune components like macrophages.^[3] Cytotoxic T cells are pivotal in immune surveillance against intracellular threats and malignancies, contributing to long-term immunity through the formation of memory CD8+ T cells that provide faster responses upon re-exposure to antigens.^[1] However, in chronic infections or tumors, they can become exhausted, marked by upregulated inhibitory receptors like PD-1 and CTLA-4, reducing their efficacy—a phenomenon targeted by immune checkpoint inhibitors in cancer immunotherapy, which have shown durable responses in over 50% of patients with metastatic melanoma.^[2] Dysregulation of these cells also underlies certain autoimmune diseases, such as type 1 diabetes, where they erroneously attack self-tissues.^[1]

Basic Biology

Definition and Characteristics

Cytotoxic T cells, also known as CD8+ T lymphocytes, are a subset of T cells in the adaptive immune system specialized for recognizing and eliminating virus-infected cells, tumor cells, and other damaged or aberrant cells through the detection of peptide antigens presented on major histocompatibility complex (MHC) class I molecules.^[1]^[2] These cells express the CD8 co-receptor, which binds to the invariant region of MHC class I, enhancing the affinity of the T cell receptor (TCR) for the peptide-MHC complex and facilitating signal transduction upon antigen encounter.^[4] The TCR on cytotoxic T cells is typically composed of α and β chains, forming a heterodimer that specifically recognizes the antigenic peptide in the context of self-MHC class I.^[5] Additionally, these cells express adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), an integrin that promotes stable interactions with target cells and antigen-presenting cells during immune surveillance.^[6] The primary functions of cytotoxic T cells include inducing apoptosis in target cells to prevent the spread of intracellular pathogens or malignant transformation, as well as secreting pro-inflammatory cytokines to amplify immune responses.^[7] Key cytokines produced include interferon-gamma (IFN-γ), which activates macrophages and enhances MHC class I expression on nearby cells, and tumor necrosis factor-alpha (TNF-α), which contributes to inflammation and direct cytotoxic effects.^[8] These effector roles position cytotoxic T cells as central mediators of cell-mediated immunity, bridging innate and adaptive responses.^[3] The discovery of cytotoxic T cells emerged in the 1960s through in vitro cytotoxicity assays demonstrating lymphocyte-mediated killing of target cells, initially observed in allograft rejection models.^[9] Pivotal advancements in the 1970s came from studies by Rolf Zinkernagel and Peter Doherty, who elucidated the MHC restriction of cytotoxic T cell responses using virus-infected mouse models, revealing that T cells recognize antigens only in the context of self-MHC molecules—a finding that earned them the 1996 Nobel Prize in Physiology or Medicine.^[10]^[11]

Distinction from Other Immune Cells

Cytotoxic T cells, also known as CD8+ T cells, are distinguished from CD4+ helper T cells primarily by their antigen recognition and functional roles in the immune response. While cytotoxic T cells recognize antigens presented by major histocompatibility complex class I (MHC I) molecules on nearly all nucleated cells, enabling them to target intracellular pathogens like viruses or abnormal cells such as tumors, helper T cells interact with MHC class II molecules expressed mainly on professional antigen-presenting cells to orchestrate broader immune responses through cytokine secretion and activation of other immune effectors.^[12]^[13] This MHC restriction reflects their complementary functions: cytotoxic T cells focus on direct cell killing via perforin and granzymes, whereas helper T cells primarily coordinate humoral and cellular immunity without direct cytotoxicity as their primary mechanism.^[14] In contrast to natural killer (NK) cells, which belong to the innate immune system and exhibit constitutive cytotoxicity without prior sensitization, cytotoxic T cells are part of the adaptive immune response and require antigen-specific priming for activation.^[15] NK cells recognize targets through germline-encoded receptors that detect stress ligands or antibody-coated cells via mechanisms like antibody-dependent cellular cytotoxicity, lacking the T cell receptor (TCR) specificity for peptide-MHC complexes that defines cytotoxic T cell responses.^[16] Furthermore, while NK cells patrol tissues continuously and respond rapidly to infections or malignancies, cytotoxic T cells undergo clonal expansion upon encountering specific antigens, generating long-lived memory populations for enhanced secondary responses.^[17] Cytotoxic T cells differ from γδ T cells in their TCR composition and antigen recognition paradigms, with the former predominantly expressing αβ TCRs restricted by classical MHC I molecules for precise peptide antigen detection.^[18] In comparison, γδ T cells utilize γδ TCRs that often operate independently of classical MHC restriction, recognizing non-peptide antigens such as phosphoantigens or stress-induced molecules on infected or transformed cells, which positions them as a bridge between innate and adaptive immunity.^[19] This MHC-independent recognition allows γδ T cells broader, less specific reactivity, whereas cytotoxic T cells' αβ TCR-MHC I interaction ensures high specificity but dependence on antigen processing and presentation.^[20] A unique feature of cytotoxic T cells among lymphocytes is their differentiation into distinct memory subsets based on homing receptor expression, such as central memory (T_CM) cells marked by CCR7+ CD45RA- phenotype, which recirculate through lymphoid organs for rapid proliferation upon re-encountering antigen, and effector memory (T_EM) cells characterized by CCR7- CD45RA- expression, enabling direct migration to inflamed peripheral tissues for immediate effector functions.^[21] These subsets, identified through surface marker analysis, underscore cytotoxic T cells' capacity for long-term surveillance and tissue-specific responses, differing from the more uniform effector profiles in NK or γδ T cells.^[22]

Development and Maturation

Thymic Development

Cytotoxic T cells, also known as CD8+ T cells, originate from hematopoietic stem cells in the bone marrow that differentiate into early T cell progenitors and migrate to the thymus for further development.^[23] These progenitors enter the thymus at the double-negative (DN) stage, characterized by the absence of CD4 and CD8 coreceptors, and constitute a small fraction of thymocytes that undergo proliferation and commitment to the T cell lineage under the influence of Notch signaling and cytokines such as IL-7.^[23] During thymic development, DN thymocytes progress through substages (DN1 to DN4) where V(D)J recombination occurs to generate a diverse T cell receptor (TCR) repertoire. TCR β-chain rearrangement happens primarily at the DN3 stage, forming a pre-TCR complex with pre-Tα and CD3 that drives survival and proliferation to the DN4 and subsequently double-positive (DP) stage, where CD4 and CD8 are co-expressed.^[23] At the DP stage, TCR α-chain rearrangement completes the αβ TCR assembly, resulting in a stochastic generation of approximately 10^15 possible TCR specificities capable of recognizing diverse peptide-MHC complexes.^[24] Positive selection occurs in the thymic cortex, where DP thymocytes interact with low-affinity self-peptides presented by MHC class I molecules on cortical thymic epithelial cells (cTECs) via their TCR and CD8 coreceptor.^[25] Thymocytes receiving appropriate survival signals upregulate Bcl-2 to evade apoptosis and differentiate toward the CD8+ lineage, ensuring the selection of T cells capable of recognizing self-MHC class I.^[25] The expression of tissue-specific self-antigens in the thymus, facilitated by the AIRE gene in medullary thymic epithelial cells (mTECs), contributes to the overall context of selection for self-tolerance, though positive selection primarily relies on cTEC-presented peptides.^[26] Negative selection follows in the thymic medulla, eliminating DP and early single-positive thymocytes with high-affinity recognition of self-antigens presented by MHC class I on mTECs, dendritic cells, or other antigen-presenting cells to prevent autoimmunity.^[25] This process induces apoptosis through activation of the pro-apoptotic protein Bim, a BH3-only member of the Bcl-2 family, which is upregulated by strong TCR signaling and commits self-reactive cells to programmed cell death.^[27] Surviving CD8+ single-positive (SP) thymocytes mature into naive T cells, downregulating CD4 while maintaining CD8 and TCR expression, and are exported from the thymus to the periphery as recent thymic emigrants to join the circulating T cell pool.^[28] This export marks the completion of intrathymic development, yielding a self-tolerant repertoire of cytotoxic T cells ready for antigen encounter.^[28]

Peripheral Maturation and Homeostasis

Naive cytotoxic T cells, also known as CD8+ T cells, circulate continuously through the blood and secondary lymphoid organs, such as lymph nodes, to surveil for foreign antigens presented by major histocompatibility complex class I molecules. This recirculation is facilitated by the expression of L-selectin (CD62L) on their surface, which mediates tethering and rolling on high endothelial venules for entry into lymph nodes, in conjunction with the chemokine receptor CCR7.^[29] Following thymic export, these naive cells maintain a quiescent state while undergoing slow, tonic signaling through their T cell receptors interacting with self-peptide/MHC complexes to support survival. Homeostasis of the naive CD8+ T cell pool is preserved through cytokine-driven self-renewal, particularly in lymphopenic environments where cell numbers are low, prompting compensatory proliferation to restore equilibrium. Interleukin-7 (IL-7) is essential for this process, promoting survival and basal proliferation by upregulating anti-apoptotic proteins like Bcl-2, while interleukin-15 (IL-15) provides additional support, especially for enhancing division rates in depleted settings.^[30] In healthy adults, these mechanisms sustain a diverse peripheral pool of naive CD8+ T cells, preventing exhaustion and ensuring repertoire diversity.^[31] Following antigen-driven activation (see Activation Process section), some naive CD8+ T cells differentiate into effector cells and, upon resolution, into long-lived memory subsets such as central memory (T_CM) and effector memory (T_EM) cells, distinguished by their migratory patterns and functional properties. T_CM cells, characterized by expression of CCR7 and CD62L, home to lymphoid tissues for rapid secondary responses, while T_EM cells downregulate these receptors and patrol peripheral tissues.^[32] Senescence in CD8+ T cells is marked by progressive telomere shortening due to repeated divisions and diminished telomerase activity, ultimately restricting replicative potential and inducing cell cycle arrest via inhibitors like p16 and p21. Co-expression of killer cell lectin-like receptor G1 (KLRG1) further signals this senescent state, particularly in terminally differentiated effector subsets, by inhibiting proliferation through tyrosine-based motifs that dampen signaling pathways such as AKT.^[33] With advancing age, thymic involution progressively diminishes naive CD8+ T cell output, shifting reliance to peripheral homeostatic mechanisms that favor memory cell accumulation. This leads to oligoclonal expansions of specific CD8+ clones, often driven by chronic viral antigens like cytomegalovirus, resulting in reduced repertoire diversity and impaired responses to new pathogens in the elderly.^[34]

Activation Process

Antigen Recognition

Cytotoxic T cells recognize antigens through their T cell receptor (TCR), which binds to peptide-major histocompatibility complex class I (pMHC I) complexes displayed on the surface of target cells. The peptides presented by MHC class I molecules are typically derived from intracellular proteins degraded by the proteasome and are usually 8-10 amino acids in length, allowing them to fit snugly into the MHC binding groove. This interaction enables cytotoxic T cells to detect infected or abnormal cells expressing foreign or altered peptides.^[35]^[36] MHC class I molecules consist of a polymorphic heavy chain with three extracellular domains (α1, α2, and α3) non-covalently associated with the invariant β2-microglobulin (β2m) light chain. The α1 and α2 domains form a closed peptide-binding groove that accommodates the antigenic peptide, while β2m stabilizes the overall structure of the complex. In humans, MHC class I alleles such as HLA-A, HLA-B, and HLA-C exhibit polymorphism primarily in the α1 and α2 domains, influencing peptide specificity and binding affinity. The crystal structure of HLA-A2 revealed this architecture, establishing the foundation for understanding pMHC I presentation.^[37] Although MHC class I typically presents endogenous peptides from intracellular sources, certain antigen-presenting cells like dendritic cells can cross-present exogenous antigens on MHC class I via specialized pathways, such as vacuolar or cytosolic routes that redirect internalized proteins for proteasomal processing. This process, first demonstrated in the context of minor histocompatibility antigen responses, allows cytotoxic T cells to initiate immunity against extracellular pathogens or tumor antigens not produced within the presenting cell itself.^[38] The affinity of TCR for pMHC I is generally low, with dissociation constants (K_D) ranging from approximately 1 to 100 μM, which contributes to the specificity and sensitivity of recognition. To amplify signaling despite this low affinity, the serial engagement model posits that a single pMHC I complex can sequentially bind and trigger multiple TCRs on the T cell surface, facilitating rapid signal propagation. This mechanism, observed through measurements of TCR internalization and calcium flux, reconciles the paradox of weak individual interactions driving robust T cell activation.^[39] The CD8 coreceptor plays a crucial role in enhancing antigen recognition by binding to the invariant α3 domain of MHC class I, thereby stabilizing the TCR-pMHC I interaction and increasing overall avidity. Additionally, CD8 recruits the Src family kinase Lck to the immunological synapse, initiating downstream phosphorylation events essential for T cell activation. This dual function of CD8 ensures efficient detection of low-abundance antigens.^[40]

Co-stimulation and Signaling

Upon engagement of the T cell receptor (TCR) with peptide-MHC class I complexes, a second signal is required for full activation of naive cytotoxic T cells, primarily provided by co-stimulatory molecules. The key co-stimulatory receptor CD28 on T cells binds to CD80 (B7-1) or CD86 (B7-2) ligands expressed on antigen-presenting cells (APCs), delivering a signal that enhances T cell survival, proliferation, and cytokine production, particularly interleukin-2 (IL-2). This interaction is essential for inducing IL-2 gene expression and secretion, which acts in an autocrine manner to sustain T cell responses; without CD28 co-stimulation, TCR signaling alone leads to anergy or apoptosis.^[41] Counterbalancing this activation, CTLA-4 serves as an inhibitory co-receptor that competes with CD28 for binding to CD80 and CD86, but with higher affinity, thereby dampening T cell responses to prevent excessive activation. CTLA-4 engagement recruits phosphatases such as PP2A, which dephosphorylate key signaling molecules, inhibiting downstream pathways and limiting IL-2 production and proliferation.^[42] This inhibitory role is critical for maintaining immune homeostasis and is upregulated following initial T cell activation. TCR and CD28 co-stimulation initiate intricate intracellular signaling cascades that integrate these signals for T cell commitment. TCR engagement phosphorylates CD3 ITAMs, recruiting and activating the kinase Zap-70, which in turn phosphorylates the adaptor protein LAT and SLP-76, forming a signalosome that activates phospholipase Cγ1 (PLCγ1). PLCγ1 hydrolyzes PIP2 to generate IP3 and DAG; IP3 induces calcium flux from intracellular stores, activating calcineurin to dephosphorylate NFAT, which translocates to the nucleus to drive transcription of activation genes like IL-2. Concurrently, DAG activates PKCθ, leading to NF-κB activation, while the Ras-MAPK/ERK pathway promotes AP-1 (c-Fos/c-Jun) formation, collectively enabling gene expression for proliferation and differentiation.^[5]^[43] The IL-2 produced binds to its high-affinity heterotrimeric receptor (IL-2Rαβγ) on activated T cells, triggering autocrine signaling via JAK1/JAK3 kinases that phosphorylate STAT5. STAT5 dimers translocate to the nucleus, promoting expression of genes like Bcl-2 for survival and cyclins for cell cycle progression, driving clonal expansion. In response to antigen, naive CD8+ T cells can undergo up to a 10,000-fold increase in numbers through this IL-2-dependent proliferation, peaking around 7-10 days post-activation before contraction.^[44]^[45] These signals also direct differentiation of activated CD8+ T cells into cytotoxic effectors, mediated by transcription factors such as Runx3, which enforces the cytotoxic lineage by repressing helper T cell genes (e.g., Cd4) and promoting expression of effectors like perforin and granzymes. Runx3 cooperates with T-box factors like T-bet to establish chromatin accessibility at cytotoxic loci, ensuring commitment to the effector program.^[46]^[47] In chronic stimulation settings, such as persistent infections or tumors, inhibitory checkpoints like PD-1 emerge to modulate these pathways and prevent overactivation. PD-1 on T cells binds PD-L1 (or PD-L2) on target cells or APCs, recruiting SHP-1/2 phosphatases that dephosphorylate CD3ζ and inhibit PI3K/Akt and Ras/ERK signaling, thereby dampening calcium flux, NFAT activation, and proliferation while promoting exhaustion-like states. This interaction fine-tunes responses in prolonged antigen exposure, balancing efficacy and tolerance.^[48]^[5]

Effector Functions

Cytotoxic Mechanisms

Activated cytotoxic T cells, also known as cytotoxic T lymphocytes (CTLs), primarily induce target cell death through two major pathways: granule exocytosis and death receptor signaling. These mechanisms are initiated upon recognition of antigenic peptides presented by major histocompatibility complex class I molecules on the target cell surface, following CTL activation. The processes occur at the interface of the immunological synapse, a specialized adhesion structure that ensures directed delivery of cytotoxic effectors.^[49] The perforin-granzyme pathway represents the dominant mechanism of rapid CTL-mediated cytotoxicity. Upon synaptic contact, CTLs release preformed lytic granules containing perforin and granzymes from their cytotoxic granules. Perforin, a pore-forming protein, polymerizes in the target cell membrane to create transmembrane pores approximately 10-20 nm in diameter, facilitating the entry of serine proteases such as granzyme B into the cytosol. Granzyme B then cleaves and activates effector caspases (e.g., caspase-3 and -7) and Bid, triggering both caspase-dependent apoptosis and mitochondrial outer membrane permeabilization, leading to rapid target cell death within minutes. This pathway is perforin-dependent and accounts for the majority of CTL killing in vivo, as demonstrated in perforin-deficient models where cytotoxicity is severely impaired.^[50]80014-2) In parallel or alternatively, CTLs employ the Fas-Fas ligand (FasL) interaction for target cell apoptosis, particularly when granule exocytosis is limited. FasL, expressed on the CTL surface or released via extracellular vesicles, binds to Fas (CD95) receptors on the target cell, recruiting the adaptor protein FADD and activating caspase-8 through the death-inducing signaling complex (DISC). This extrinsic pathway initiates caspase cascades independent of perforin and granzymes, though it is slower (typically 1-2 hours) and can synergize with the granzyme pathway for enhanced killing. The Fas-FasL mechanism is crucial for eliminating activated immune cells and certain virally infected targets resistant to granule-mediated death.80014-2) Effective cytotoxicity requires stable cell-cell contact mediated by the immunological synapse. This structure forms through adhesion molecules such as LFA-1 (on CTL) binding ICAM-1 (on target), stabilizing the interface and polarizing the CTL's microtubule-organizing center toward the synapse for directed granule release. The synapse segregates signaling (central supramolecular activation cluster) from secretory domains (peripheral), ensuring precise delivery of cytotoxic molecules while minimizing bystander damage.81716-6) To prevent self-inflicted damage during effector release, CTLs express protective mechanisms including serine protease inhibitors. Cytoplasmic serpin PI-9 (serpin B9) specifically inhibits granzyme B, blocking its autocatalytic activity and caspase activation within the CTL itself. Additionally, low pH in endolysosomal compartments and binding to serglycin inactivate perforin, confining its activity to the target membrane. These safeguards enable sustained CTL function without apoptosis.^[49] Quantitatively, a single activated CTL can sequentially eliminate up to 10-20 target cells over several hours, replenishing lytic granules between killings via degranulation cycles. This serial killing capacity amplifies immune responses, allowing efficient clearance of infected or malignant cells in vivo.

Cytokine Production and Modulation

Cytotoxic T cells, particularly those of the Tc1 subset, primarily secrete interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) as key cytokines that coordinate broader immune responses. IFN-γ activates macrophages to enhance phagocytosis and antimicrobial activity while upregulating major histocompatibility complex class I (MHC I) expression on target cells, thereby amplifying antigen presentation and immune surveillance.^[23]^[51] TNF-α contributes to inflammation by recruiting additional immune cells and directly induces apoptosis in infected or malignant cells through receptor-mediated signaling.^[52]^[53] In contrast to Th2-associated cytokines, Tc1 cells produce only minimal amounts of interleukin-4 (IL-4) and IL-10, reinforcing their pro-inflammatory, type 1 immune bias that prioritizes pathogen clearance over suppression.^[52]^[54] The production of these cytokines is driven by transcriptional polarization following T cell activation, with the T-box transcription factor T-bet playing a central role in committing CD8+ T cells to the Tc1 phenotype. T-bet expression is induced by signals such as IL-12 and promotes the chromatin remodeling necessary for IFN-γ and TNF-α gene transcription, ensuring robust effector responses.^[55]^[56] This mechanism allows cytotoxic T cells to rapidly amplify their secretory output upon antigen encounter, integrating direct cytotoxicity with soluble factors that shape the immune microenvironment. Through cytokine secretion, cytotoxic T cells modulate the activity of other immune components, including enhancing natural killer (NK) cell cytotoxicity via IFN-γ signaling that boosts NK degranulation and target cell killing.^[57]^[58] Indirectly, IFN-γ from these T cells promotes B cell class switching toward IgG2a and IgG3 isotypes by inducing T-bet expression in B cells, thereby supporting humoral immunity against intracellular pathogens.^[59] Additionally, cytotoxic T cells secrete chemokines such as CXCL9 and CXCL10, which bind CXCR3 on effector T cells and NK cells to recruit further reinforcements to infection or tumor sites.^[52]^[60] Cytokine profiles exhibit variability across cytotoxic T cell subsets, with short-lived effector cells generally producing higher levels of IFN-γ compared to long-lived memory cells, reflecting their role in acute, high-intensity responses.^[61]^[62] Memory cells, while capable of rapid IFN-γ recall upon re-exposure, maintain lower baseline production to support persistence and self-renewal.^[63] This subset-specific modulation ensures balanced immunity, preventing excessive inflammation while preserving effector potential.

Roles in Immunity

Antiviral and Antibacterial Defense

Cytotoxic T cells, also known as CD8+ T cells, play a pivotal role in antiviral defense by recognizing and eliminating virus-infected cells through antigen-specific mechanisms. In acute infections such as influenza, HIV, and cytomegalovirus (CMV), these cells rapidly expand and target viral antigens presented on major histocompatibility complex class I (MHC-I) molecules, leading to the lysis of infected host cells and thereby limiting viral replication. For instance, during acute HIV infection, HLA-A2-restricted cytotoxic T lymphocytes (CTLs) recognize epitopes derived from the HIV gag protein, such as the SLYNTVATL peptide, enabling precise targeting of infected cells and contributing to the initial decline in viremia. Similarly, in influenza A virus infection, CD8+ T cells directed against conserved nucleoprotein epitopes facilitate clearance by inducing apoptosis in infected respiratory epithelial cells. In CMV infections, HCMV-specific CD8+ CTLs are essential for controlling viral replication and preventing disseminated disease, particularly in immunocompromised individuals, through sustained surveillance and effector responses. Overall, the activation of these epitope-specific CD8+ T cells during acute viral infections can reduce viral loads by 2-3 logs, marking a critical phase of immune control before potential transition to chronicity or resolution. Beyond viruses, cytotoxic T cells contribute to defense against intracellular bacterial pathogens, such as Listeria monocytogenes and Mycobacterium tuberculosis, by deploying granzyme-mediated killing to disrupt bacterial survival within host cells. In Listeria infections, CD8+ T cells infiltrate infected tissues and release granzymes that degrade bacterial virulence factors secreted into the cytosol, thereby attenuating pathogen spread and promoting bacterial clearance from macrophages and hepatocytes. For Mycobacterium tuberculosis, human CD8+ CTLs express granulysin and granzyme B, which target intracellular mycobacteria by perforating phagosomal membranes and inducing infected cell death, thus restricting bacterial persistence in granulomas. These mechanisms highlight the versatility of cytotoxic T cells in combating bacteria that evade humoral immunity by residing within host cells. A key aspect of cytotoxic T cell-mediated protection is the formation of long-lived memory CD8+ T cells, which provide rapid recall responses upon re-exposure to the same pathogen. These memory cells persist for decades after primary infection or vaccination, maintaining a poised state that allows for 10-100 times faster proliferation compared to naive T cells, enabling swift differentiation into effectors that control reinfection. This memory function is exemplified in resolved viral infections like influenza, where memory CD8+ T cells confer heterosubtypic immunity by rapidly expanding to limit viral titers upon challenge with variant strains. The implications of cytotoxic T cell responses extend to vaccine design, particularly live-attenuated vaccines that mimic natural infection to induce robust CD8+ T cell immunity. The yellow fever 17D vaccine (YF-17D), one of the most efficacious vaccines available with over 99% seroconversion rates, elicits a broad and polyfunctional memory CD8+ T cell response targeting multiple viral epitopes, which correlates with long-term protection against severe disease. This vaccine-induced CD8+ T cell compartment persists for years, providing a model for developing similar responses against other intracellular pathogens.

Antitumor Surveillance

Cytotoxic T cells play a pivotal role in antitumor surveillance by recognizing and eliminating malignant cells that arise from transformed host tissues. These cells, primarily CD8+ T lymphocytes, patrol peripheral tissues and detect aberrant proteins expressed by tumors through major histocompatibility complex class I (MHC I) molecules on the surface of cancer cells. This process is essential for preventing the outgrowth of nascent tumors and maintaining immune control over established malignancies.^[2] Tumor antigens recognized by cytotoxic T cells include neoantigens, which are novel peptides generated from somatic mutations in cancer cells and presented via MHC I to activate antigen-specific T cell responses. For instance, in cancers driven by oncogenic viruses, such as human papillomavirus (HPV)-associated cervical cancer, viral oncoproteins like E6 and E7 are processed and displayed on MHC I, enabling cytotoxic T cells to target infected and transformed cells. This recognition triggers T cell activation and subsequent cytotoxic responses, highlighting the specificity of antitumor immunity.^[64]^[65]^[66] Once activated, cytotoxic T cells infiltrate tumors as tumor-infiltrating lymphocytes (TILs), guided by chemokine receptors such as CXCR3, which binds to ligands like CXCL9 and CXCL10 produced in the tumor microenvironment to facilitate homing and accumulation at the site of malignancy. Upon infiltration, TILs exert perforin-dependent cytotoxicity, releasing perforin and granzymes to induce apoptosis in target cancer cells, thereby promoting tumor regression. This mechanism is critical for the direct elimination of antigen-expressing tumor cells within solid tumors.^[67]30190-6)^[68] In the immunoediting process, cytotoxic T cells contribute to an equilibrium phase where chronic immune recognition keeps tumors in a dormant state, suppressing their progression through ongoing surveillance and selective pressure on antigen-expressing cells. This phase precedes potential tumor escape, where less immunogenic variants may emerge. Evidence from mouse models supports this role; for example, MHC I-deficient tumors exhibit accelerated growth and increased incidence in immunocompetent hosts, underscoring the necessity of MHC I presentation for T cell-mediated control.01199-0)00230-9) Human studies further validate these findings, as adoptive transfer of TILs in melanoma patients has led to objective tumor regressions, with durable responses correlating to the persistence of neoantigen-specific cytotoxic T cells. However, challenges persist due to tumor heterogeneity, which can generate antigen loss variants that evade T cell recognition, allowing immune escape and tumor progression despite initial surveillance.^[69]00413-8)00225-8)

Involvement in Pathology

Autoimmune and Inflammatory Diseases

Dysregulated cytotoxic T cells, or CD8+ T cells, contribute to autoimmune and inflammatory diseases by escaping central tolerance mechanisms, such as negative selection in the thymus, allowing autoreactive clones to persist and infiltrate target tissues.^[70] These autoreactive CD8+ T cells recognize self-antigens presented by MHC class I molecules, leading to direct cytotoxicity against healthy cells through pathways like perforin/granzyme release or Fas-Fas ligand (FasL) interactions.^[71] In type 1 diabetes, for instance, CD8+ T cells specific for β-islet cell antigens escape negative selection and mediate β-cell destruction via FasL-induced apoptosis, as demonstrated in NOD mouse models and human studies.^[72] In rheumatoid arthritis, cytotoxic CD8+ T cells infiltrate the synovium, where they target citrullinated antigens in an HLA class I-dependent manner, promoting joint inflammation and tissue damage through granzyme B and granulysin expression.^[73] Similarly, in multiple sclerosis, CD8+ T cells predominate in central nervous system lesions, often outnumbering CD4+ T cells with ratios up to approximately 6-fold in some progressive cases, and drive demyelination by recognizing myelin-derived peptides and inducing axonal transection via MHC class I-restricted cytotoxicity.^[74]^[75] In celiac disease, gliadin-specific CD8+ T cells, restricted by HLA class I alleles like HLA-A2, activate in the intestinal mucosa, releasing granzyme B and IFN-γ to induce enterocyte apoptosis and exacerbate villous atrophy.^[76] Cytotoxic T cells amplify inflammation in diseases like inflammatory bowel disease through IFN-γ production, which disrupts epithelial barriers, promotes apoptosis, and enhances permeability, often in synergy with CD4+ T cells.^[77] Genetic factors, including HLA associations, further predispose to CD8+ T cell-mediated pathology; for example, HLA-B27-restricted autoreactive CD8+ T cells recognizing self-epitopes correlate with ankylosing spondylitis, contributing to spinal inflammation.^[78] Overall, CD8+ T cells play a substantial role in organ-specific autoimmunity, often collaborating with CD4+ T cells to drive disease progression in conditions affecting 5-10% of the population worldwide.^[71]

Transplant Rejection and Immunodeficiencies

Cytotoxic T cells, also known as CD8+ T cells, play a central role in acute transplant rejection through direct allorecognition, where they recognize intact foreign major histocompatibility complex class I (MHC I) molecules on donor graft cells, triggering rapid cytotoxic responses that damage the allograft.^[79] This process is mediated by the T cell receptor binding to allogeneic MHC I-peptide complexes on graft endothelial and parenchymal cells, leading to perforin and granzyme release that induces apoptosis in target cells.^[80] In parallel, indirect allorecognition occurs when host antigen-presenting cells (APCs) process and present donor-derived peptides on self-MHC I molecules to CD8+ T cells, amplifying the immune response and contributing to graft infiltration and dysfunction during the early post-transplant period.^[80] These mechanisms dominate cellular rejection episodes, often occurring within the first year after transplantation. In chronic transplant rejection, cytotoxic T cells contribute to progressive vascular damage, particularly in heart and kidney allografts, through sustained perforin-mediated endothelial cell death, which promotes transplant vascular disease (TVD) characterized by intimal thickening and luminal narrowing.^[81] Perforin release from CD8+ T cells and natural killer cells targets vascular endothelium, leading to chronic inflammation and fibrosis that impair long-term graft function, with TVD being a primary cause of late allograft failure in solid organ transplants.^[82] This perforin-dependent pathway underscores the persistent alloimmune activity of cytotoxic T cells in maintaining low-grade rejection over years. In immunodeficiencies, cytotoxic T cell function and numbers are severely compromised; for instance, in HIV infection, gp120-mediated mechanisms induce apoptosis in activated CD8+ T cells via interactions with chemokine receptors like CXCR4 on macrophages, resulting in progressive reduction of naive CD8+ T cell counts during the asymptomatic phase.^[83] In severe combined immunodeficiency (SCID), thymic developmental defects, such as those in genes regulating T cell maturation, lead to profound reductions in circulating CD8+ T cells due to impaired positive selection and differentiation in the thymus.^[84] Advanced HIV progression to AIDS further exacerbates this through functional exhaustion of remaining CD8+ T cells, marked by impaired cytokine production, reduced proliferative capacity, and upregulation of inhibitory receptors like PD-1, diminishing their antiviral and cytotoxic potential despite initial expansions.^[85] Diagnostic evaluation of cytotoxic T cell involvement in these contexts includes enzyme-linked immunospot (ELISPOT) assays, which quantify alloreactive CD8+ T cell frequencies by measuring interferon-gamma secretion in response to donor antigens, serving as a predictive tool for acute rejection risk in transplant candidates.^[86] In primary immunodeficiencies, CD8+ lymphopenia is a key marker reflecting underlying thymic or developmental impairments that can be confirmed via flow cytometry.^[87] Cytotoxic T cells dominate cellular rejection mechanisms, with CD8+ responses driving the majority of T cell-mediated allograft damage, contributing to acute rejection rates of 10-20% within the first post-transplant year that, if untreated, progress to chronic failure.^[88] This CD8+ dominance highlights their critical pathological role, as elevated alloreactive frequencies correlate with poorer long-term outcomes in kidney and heart transplants.^[79]

Clinical and Therapeutic Applications

T Cell Exhaustion and Regulation

T cell exhaustion represents a progressive loss of effector functions in cytotoxic T cells (CD8+ T cells) during chronic infections or cancer, characterized by diminished cytokine production, reduced proliferation, and impaired cytotoxicity in response to persistent antigen stimulation. This state is marked by the upregulation of inhibitory receptors such as PD-1, TIM-3, and LAG-3 on the T cell surface, which transmit signals that dampen T cell activation and effector responses.^[89]^[90]^[91] At the molecular level, exhaustion is driven by epigenetic and transcriptional reprogramming, with the transcription factor TOX playing a central role in establishing and maintaining this dysfunctional state. TOX induces chromatin accessibility changes that promote the expression of exhaustion-associated genes, including those encoding inhibitory receptors, while simultaneously reducing responsiveness to cytokines and growth factors like IL-2. This leads to a self-reinforcing loop where exhausted T cells exhibit altered metabolic profiles, favoring survival over robust effector activity.^[92]^[90]^[89] Regulation of cytotoxic T cell activity to prevent overactivation involves multiple mechanisms, including suppression by regulatory T cells (Tregs), which express CTLA-4 to compete with effector T cells for binding to CD80 and CD86 on antigen-presenting cells, thereby depriving effectors of costimulatory signals. Tregs also secrete immunosuppressive cytokines such as IL-10 and TGF-β, which further inhibit effector T cell proliferation and cytokine secretion through feedback loops involving STAT3 and SMAD signaling pathways.^[93]^[94]^[95] Strategies to reverse T cell exhaustion have focused on epigenetic modifiers, with recent research highlighting the role of TET2 mutations in influencing exhaustion propensity by altering DNA methylation patterns that affect T cell differentiation trajectories. In preclinical models, TET2 deficiency has been shown to delay exhaustion onset and enhance antitumor efficacy in engineered T cells, suggesting potential therapeutic targeting to restore function in chronic settings.^[96]^[97] Clinically, T cell exhaustion is commonly observed in chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, where it contributes to viral persistence and is associated with treatment failure in the majority of cases by limiting effective immune clearance.^[98]^[99]^[100]

Immunotherapies and CAR-T Cells

Immunotherapies leveraging cytotoxic T cells have revolutionized cancer treatment by enhancing their antitumor activity. Checkpoint inhibitors, such as anti-PD-1 antibodies, block inhibitory signals that lead to T cell exhaustion, thereby reinvigorating cytotoxic T cells against tumors. Pembrolizumab, approved by the FDA in 2014 for advanced melanoma, demonstrated objective response rates of 21-34% in patients with melanoma refractory to targeted therapies. In non-small cell lung cancer with PD-L1 TPS ≥1%, pembrolizumab achieved an objective response rate of 27% as first-line therapy (KEYNOTE-042), with 45% in PD-L1 TPS ≥50% patients (KEYNOTE-024), and durable responses observed in PD-L1-positive patients. These therapies have shown response rates ranging from 20-40% across melanoma and lung cancer indications, highlighting their role in prolonging survival by unleashing endogenous cytotoxic T cell responses.^[101]^[102] Chimeric antigen receptor (CAR) T cell therapy represents a cornerstone of adoptive immunotherapy, where patient-derived T cells are genetically engineered to express CARs that redirect cytotoxic T cells to tumor antigens. The CAR structure typically includes a single-chain variable fragment (scFv) for antigen recognition, such as CD19 in B-cell malignancies, linked to intracellular signaling domains like CD3ζ for activation and co-stimulatory domains such as 4-1BB for enhanced persistence. Tisagenlecleucel, the first CAR-T therapy approved by the FDA in 2017 for relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in patients up to 25 years old, targets CD19 and has induced remissions in over 80% of eligible pediatric and young adult patients, with complete remissions in 60% (ELIANA trial). This approach has transformed outcomes in hematologic cancers by enabling precise, potent cytotoxic killing of antigen-expressing cells.^[103] Adoptive cell transfer using tumor-infiltrating lymphocytes (TILs) involves extracting, expanding, and reinfusing tumor-specific cytotoxic T cells from patient tumors, often following lymphodepleting chemotherapy to enhance engraftment. Clinical trials post-2010 have reported objective response rates of up to 50% in patients with metastatic melanoma treated with TIL therapy, with some achieving durable complete remissions. In February 2024, the FDA approved lifileucel (LN-144), the first TIL therapy for solid tumors, for adult patients with unresectable or metastatic melanoma previously treated with a PD-1 inhibitor and, if applicable, BRAF V600-targeted therapy, based on a 31.4% ORR from the phase 2 C-144-01 trial.^[104] This method harnesses naturally occurring cytotoxic T cells reactive to tumor neoantigens, offering a personalized strategy particularly effective in immunogenic tumors like melanoma. Recent advances extend cytotoxic T cell therapies to broader applications, including T cell receptor (TCR)-engineered T cells and bispecific antibodies. TCR-engineered T cells targeting cancer-testis antigens like NY-ESO-1 have shown promise in phase I/II trials for solid tumors, such as melanoma and synovial sarcoma, with objective responses observed in over 50% of NY-ESO-1-positive patients across studies involving more than 100 participants. Bispecific T cell engagers, exemplified by blinatumomab, a CD19/CD3 bispecific antibody approved for B-ALL, redirect cytotoxic T cells to lyse CD19-positive tumor cells by simultaneously binding tumor antigens and CD3 on T cells, achieving complete remission rates of 40-45% in relapsed patients. These innovations address limitations in solid tumors by improving T cell trafficking and activation. Despite their efficacy, cytotoxic T cell therapies face challenges including cytokine release syndrome (CRS), a potentially life-threatening inflammatory response managed primarily with tocilizumab, an IL-6 receptor antagonist that rapidly resolves severe CRS without impairing T cell function. In hematologic malignancies, CAR-T therapies have led to 5-year overall survival improvements of up to 50% in select B-ALL and lymphoma cohorts, underscoring their transformative impact while necessitating vigilant toxicity monitoring.

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