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CD8

CD8 is a transmembrane glycoprotein co-receptor expressed primarily on the surface of cytotoxic T lymphocytes (CTLs), where it binds to the α3 domain of major histocompatibility complex class I (MHC-I) molecules to stabilize the interaction between the T-cell receptor (TCR) and peptide-MHC-I complexes, thereby enhancing antigen-specific T-cell activation and signaling.^[1] This co-receptor plays a critical role in adaptive immunity by facilitating the maturation of CD8+ T cells in the thymus, promoting their cytotoxic functions against virally infected cells and tumors, and contributing to immune surveillance through serial killing mechanisms.^[2] CD8 exists in two main isoforms: the CD8αβ heterodimer, predominant on conventional CTLs and essential for TCR signaling via recruitment of the kinase Lck, and the CD8αα homodimer, found on intraepithelial lymphocytes and thymocytes, which supports interactions with nonclassical MHC molecules.^[1] Structurally, CD8 is a disulfide-linked dimer with each subunit featuring an extracellular immunoglobulin-like domain, a glycosylated hinge region, a transmembrane domain, and a short cytoplasmic tail that associates with Lck to amplify downstream signaling pathways upon antigen encounter.^[3] Beyond T cells, CD8 is expressed on subsets of natural killer (NK) cells, dendritic cells, and γδ T cells, where it modulates effector functions such as cytokine production and cytotoxicity, and recent studies highlight its role in enhancing responsiveness in mucosal-associated invariant T (MAIT) cells via MR1 presentation.^[1] Therapeutically, CD8 serves as a target for immunomodulation, with monoclonal antibodies capable of blocking or depleting CD8+ T cells to treat autoimmune disorders or enhancing antitumor immunity in cancer immunotherapy.^[2]

Discovery and Overview

Historical Discovery

The identification of CD8 as a marker for cytotoxic T cells emerged from foundational studies in the 1970s using mouse models, where the Lyt-2 and Lyt-3 antigens were recognized on effector cells responsible for cytotoxicity. These antigens were distinguished through serological analyses and functional assays, revealing that Lyt-2+,3+ T cells mediated cell-mediated cytotoxicity against allogeneic targets, while Lyt-1+ cells supported helper functions. Early experiments in the same decade linked these subsets to sheep red blood cell (SRBC) rosetting, a technique initially used to enumerate T lymphocytes, with subsequent work demonstrating that rosette-forming cells enriched for cytotoxic activity in response to viral or tumor antigens. In humans, the late 1970s and early 1980s saw the development of monoclonal antibodies that enabled precise dissection of T cell subsets. Antibodies such as OKT8, generated by immunizing mice with human thymocytes, specifically labeled the cytotoxic/suppressor T cell population, distinguishing it from the helper subset marked by OKT4. Similarly, Leu-2 antibodies, produced against T cell-enriched fractions, targeted the same population and inhibited cytotoxic functions in vitro. These reagents facilitated the separation of functional subsets via fluorescence-activated cell sorting and complement-mediated lysis, confirming their role in distinguishing cytotoxic from helper T cells. A pivotal advancement occurred in 1980 when Ellis L. Reinherz and Stuart F. Schlossman isolated the CD8 molecule (then termed the T8 antigen) through immunoprecipitation of surface-labeled human T lymphocytes using OKT8 and related antibodies. Biochemical analysis revealed T8 as a 50,000–60,000 molecular weight glycoprotein, distinct from the T4 antigen on helper cells, and expressed on approximately 30% of peripheral T lymphocytes. This work established CD8's identity as a core marker for the cytotoxic/suppressor lineage.^[4] The standardized nomenclature for CD8 evolved from the mouse Lyt-2/3 designation through the First International Workshop on Human Leukocyte Differentiation Antigens, held in Paris in 1982. This collaborative effort evaluated over 130 monoclonal antibodies, clustering those recognizing the same 32–34 kDa glycoprotein on cytotoxic T cells as CD8, thereby unifying terminology across species and facilitating global research.^[5]

Molecular Definition and Isoforms

CD8 is a dimeric glycoprotein that functions as a co-receptor in the immune system, encoded by two closely linked genes, CD8A and CD8B, both located on the short arm of human chromosome 2 at position 2p11.2.^[6]^[7] The CD8A gene produces the alpha chain, a 235-amino-acid polypeptide, while the CD8B gene encodes the beta chain, comprising 210 amino acids.^[8]^[9] These chains share structural similarities, including an extracellular immunoglobulin-like domain, a hinge region, a transmembrane segment, and a cytoplasmic tail, but differ in their expression patterns and associations.^[8]^[9] The predominant isoform of CD8 is the αβ heterodimer, formed by disulfide linkage between the alpha and beta chains, and is primarily expressed on the surface of cytotoxic CD8+ T lymphocytes, where it enhances T cell receptor signaling.^[8] Alternative isoforms include the αα homodimer, which assembles via similar disulfide bonds and is expressed on subsets of intraepithelial lymphocytes and γδ T cells, contributing to mucosal and innate-like immune responses.^[10] A less common ββ homodimer has also been described but is not widely observed in human cells.^[1] Post-translational modifications are critical for CD8 stability and function. Both chains undergo N-linked glycosylation at conserved asparagine residues in the extracellular domain—specifically, Asn102 in the alpha chain—adding carbohydrate moieties that influence folding, trafficking, and surface expression.^[8] The beta chain features potential O-linked glycosylation sites in its stalk region, further modulating dimer formation.^[11] Disulfide bonds play a key role in stabilizing these isoforms: an intramolecular bond in the immunoglobulin domain of each chain maintains the fold, while intermolecular cysteines in the hinge region link the subunits in both heterodimers and homodimers.^[1] A soluble form of CD8, primarily the alpha chain variant, is generated through alternative splicing of CD8A transcripts, resulting in exclusion of the exon encoding the transmembrane domain and leading to a secreted glycoprotein detectable in serum, particularly during immune activation. This isoform may modulate immune responses by acting as a decoy receptor or regulator of T cell activity.

Structure

Overall Architecture

CD8 functions as a transmembrane glycoprotein dimer on the surface of cytotoxic T cells and natural killer cells, primarily in the form of an αβ heterodimer, though αα homodimers also occur. Each chain consists of an extracellular immunoglobulin-like domain, a proline-rich hinge region that provides flexibility, a single-span transmembrane helix, and a short cytoplasmic tail. The overall structure positions the dimer to bridge the T cell receptor complex with major histocompatibility complex class I (MHC-I) molecules on antigen-presenting cells, facilitating co-receptor activity.^[2] The crystal structure of the recombinant mouse CD8αβ ectodomain, resolved at 2.4 Å resolution in 2005 (PDB: 2ATP), demonstrates that both the α and β chains feature V-set immunoglobulin-like domains with similar β-sandwich folds, forming an elongated, stalk-like assembly connected by the hinge. This configuration allows the domains to extend rigidly from the membrane while permitting rotational freedom at the hinge for optimal MHC-I engagement.^[12]^[13] Dimerization is mediated by non-covalent interactions at the interface of the extracellular immunoglobulin domains, primarily involving hydrophobic contacts and hydrogen bonds between conserved residues in the α and β chains. This interface is further reinforced by a conserved intermolecular disulfide bond formed between cysteine residues in the transmembrane domains of the α and β chains, ensuring stable anchoring and orientation within the lipid bilayer. The single-span α-helical transmembrane segments, approximately 20-25 residues long, embed the dimer perpendicularly into the plasma membrane.^[2]

Domains and Chains

The CD8 co-receptor consists of α and β chains, each featuring distinct modular domains that contribute to its overall function in T cell signaling. The extracellular domain of CD8α comprises an immunoglobulin V-set motif spanning residues 22–125, which is primarily responsible for binding to the α3 domain of MHC class I molecules, facilitating co-receptor engagement during antigen recognition. In contrast, the CD8β extracellular domain contains a V-set immunoglobulin motif from residues 22–129, which enhances the stability of the αβ heterodimer without direct MHC contact, thereby supporting efficient dimer formation as described in the overall architecture.^[2] Connecting the extracellular Ig domains to the membrane is the hinge region, a flexible linker of approximately 10–20 residues rich in proline and serine/threonine for O-glycosylation, which imparts mobility to the CD8 ectodomain. This flexibility is crucial for allowing the CD8 dimer to position optimally relative to the TCR-MHC class I complex, accommodating variations in the immune synapse geometry without rigid constraints.^[2]^[12] The transmembrane domain of both chains forms a hydrophobic α-helix of about 20 residues, enabling stable insertion into the lipid bilayer and anchoring the co-receptor to the T cell surface. For CD8α, this spans residues 183–203, while for CD8β it covers 171–191; a membrane-proximal cysteine in each forms an intermolecular disulfide bond that further stabilizes the heterodimer.^[2] The cytoplasmic tails are short, with the CD8α tail comprising 32 residues (204–235) and the CD8β tail 19 residues (192–210), and exhibit chain-specific features for signaling recruitment. The CD8α tail lacks an ITAM but contains basic motifs, including a CXCP sequence, that mediate association with the Src family kinase Lck to initiate downstream signaling upon co-receptor ligation. The CD8β tail includes palmitoylation sites that contribute to localization in lipid rafts and modulation of Lck activity, distinguishing its role in fine-tuning T cell activation from the α chain.^[14]^[2]^[1]

Expression and Distribution

Cellular Expression Patterns

CD8 is primarily expressed on cytotoxic CD8+ T cells, where it exists predominantly as an αβ heterodimer, facilitating their role in immune surveillance within circulating blood, lymph nodes, and the spleen.^[2] These cells represent the main population bearing this isoform, enabling antigen-specific recognition and cytotoxic responses.^[15] In secondary expression sites, CD8 appears as an αα homodimer on natural killer (NK) cells, which contribute to innate immunity, as well as on intestinal intraepithelial lymphocytes (IELs) that patrol mucosal barriers and certain subsets of γδ T cells involved in rapid responses at epithelial interfaces.^[2] CD8 is also expressed on subsets of dendritic cells, where it modulates functions such as antigen presentation.^[1] This homodimeric form supports distinct functions in these non-conventional lymphocytes, differing from the heterodimer's role in conventional T cells.^[15] Tissue distribution of CD8 is concentrated in the thymus, where it marks developing T cells, and in peripheral lymphoid organs such as lymph nodes and spleen, reflecting sites of T cell maturation and activation; expression remains low or absent in B cells, macrophages, and most non-hematopoietic tissues.^[2] During thymocyte development, CD8 expression is upregulated at the immature single-positive stage and peaks in the double-positive (CD4+CD8+) compartment, where it aids in positive selection, before being retained on mature CD8+ single-positive cells while downregulated on naive CD4+ T cells.^[16]^[17]

Regulation of Expression

The expression of CD8 is primarily controlled at the transcriptional level through lineage-specific transcription factors that bind to promoter and enhancer regions of the CD8A and CD8B genes. In the cytotoxic T cell lineage, the transcription factor Runx3 upregulates CD8 expression by directly binding to silencer elements in the Cd4 locus and activating Cd8a and Cd8b transcription during positive selection in the thymus.^[18] Conversely, ThPOK (also known as Zbtb7b) represses CD8 expression in the CD4 helper T cell lineage by antagonizing Runx3 activity and directly inhibiting CD8 promoters, thereby ensuring lineage fidelity during thymocyte differentiation.^[19] These factors coordinate with other regulators, such as Ets1, to fine-tune CD8 levels in response to T cell receptor signaling strength.^[20] Epigenetic modifications further govern CD8 expression by altering chromatin accessibility at the CD8A and CD8B loci during T cell development. Histone acetylation, particularly at H3K14 mediated by the bromodomain-containing protein Brd1, promotes an open chromatin conformation that facilitates CD8 gene activation in differentiating cytotoxic T cells.^[21] In contrast, DNA methylation at CpG islands in the CD8 promoters silences expression in non-T cells and double-negative thymocytes, with demethylation occurring progressively during the double-positive stage to permit lineage-appropriate activation; this silencing is maintained by DNA methyltransferases like Dnmt1 in cells outside the TCRαβ lineage.^[22] Post-transcriptional mechanisms, including microRNA-mediated control, regulate CD8 mRNA stability and translation efficiency in T cells. MicroRNAs such as miR-181a modulate T cell sensitivity to antigens by targeting phosphatases like DUSP6, indirectly influencing CD8 surface expression through enhanced TCR signaling during activation.^[23] Additionally, cytokines like IL-2 promote the activation and expansion of CD8+ T cells via STAT5 signaling.^[24] Environmental cues, particularly during thymic selection and peripheral activation, stabilize CD8 expression on mature cytotoxic T cells. Antigen exposure via MHC class I during positive selection in the thymus induces sustained CD8 transcription and surface maintenance, ensuring functional maturity in the CD8 lineage. This regulation is most prominent in cytotoxic T lymphocytes, where stable expression supports effector functions.

Function

Role in T Cell Activation

CD8 serves as a co-receptor for the T cell receptor (TCR) on cytotoxic T lymphocytes (CTLs), binding to non-polymorphic regions of MHC class I molecules on antigen-presenting cells and thereby stabilizing the TCR-MHC class I interaction. This bidentate binding—where both TCR and CD8 attach to the same MHC molecule—increases the overall avidity of the TCR-pMHC complex, enhancing the sensitivity of T cells to low-affinity peptide antigens and facilitating effective immune surveillance.^[25] Upon ligation, CD8 recruits the Src family kinase Lck to the TCR complex, as Lck is constitutively associated with the cytoplasmic tail of CD8. This recruitment positions Lck in proximity to the CD3 chains of the TCR, enabling phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) and initiating downstream signaling cascades essential for T cell activation. In this manner, CD8 amplifies TCR signals, lowering the activation threshold and promoting robust CTL responses to infected or malignant cells.^[26] During CTL-mediated cytotoxicity, CD8 localizes to the periphery of the immune synapse formed between the T cell and target cell, stabilizing the interaction and directing the polarized release of cytotoxic granules containing perforin and granzymes toward the target. This positioning ensures efficient delivery of lytic molecules across the synaptic cleft, inducing apoptosis in MHC class I-presenting cells while sparing bystander tissues.^[27]^[28]

Role in Natural Killer Cells

CD8 is expressed on a subset of human natural killer (NK) cells primarily as the αα homodimer, in contrast to the predominant αβ heterodimer form observed on conventional cytotoxic T cells. Approximately 40% of human NK cells (with a range of 15%–88% across individuals) display surface CD8αα, while only a small fraction (1%–2%) express the CD8αβ heterodimer. This homodimeric expression distinguishes NK cell CD8 from its co-receptor role in T cells and contributes to NK-specific functions independent of T cell receptor signaling. In NK cells, CD8αα modulates cytotoxicity by acting as a coreceptor for inhibitory killer cell immunoglobulin-like receptors (KIRs), such as KIR3DL1, thereby stabilizing the balance between inhibitory and activating signals. This interaction with MHC class I molecules fine-tunes NK cell responsiveness, enhancing the effectiveness of activating receptors like NKG2D in targeting virus-infected or tumor cells that upregulate NKG2D ligands. By facilitating NK cell licensing through strengthened KIR-MHC binding, CD8αα ensures calibrated cytotoxicity, preventing overactivation while promoting robust responses against aberrant targets. CD8 also supports antibody-dependent cellular cytotoxicity (ADCC) in NK cells by associating with the CD16-bright subset, which exhibits heightened expression of FcγRIIIa (CD16) and superior cytotoxic potential. CD8α+ NK cells, comprising the majority of CD56^dim CD16^bright effectors, demonstrate improved survival during prolonged killing assays and efficient granzyme delivery upon CD16 engagement by IgG-opsonized targets. This enhances ADCC-mediated elimination of antibody-coated cells, such as infected or malignant targets. As a differentiation marker, CD8αα identifies licensed NK cell subsets with tuned responsiveness to self-MHC class I, reflecting their education status that calibrates inhibitory thresholds for optimal function. CD8α+ NK cells often show MHC-dependent surface expression dynamics and contribute to enhanced signaling through self-MHC interactions, distinguishing them from unlicensed counterparts with hyporesponsiveness. This marking aids in identifying NK populations poised for effective innate surveillance.

Interactions and Signaling

Binding to MHC Class I

The CD8 co-receptor binds to major histocompatibility complex (MHC) class I molecules primarily through its α chain's V-set immunoglobulin-like domain, which interacts with the α3 domain of MHC class I. This binding site involves the complementarity-determining region (CDR)-like loops of CD8α (residues 51–55), which contact a flexible loop in the MHC α3 domain (residues 223–229, such as in HLA-A*0201). Conserved residues facilitate this interaction via electrostatic complementarity; for instance, negatively charged residues like Gln226 and Glu222 in the MHC α3 domain form salt bridges and hydrogen bonds with basic residues in CD8α, ensuring stable yet dynamic association independent of the bound peptide.^[29]^[3] The affinity of the CD8-MHC class I interaction is characteristically low in solution, with dissociation constants (Kd) typically ranging from 100–220 μM for human CD8αα and similar values (49–69 μM on average) for murine CD8αβ, reflecting rapid on-off kinetics that prevent non-specific adhesion while allowing serial engagement. However, this binding is cooperative with the T cell receptor (TCR)-peptide-MHC class I interaction; the combined avidity of the ternary complex increases dramatically to the nanomolar range, enhancing overall T cell sensitivity to antigens by up to 100-fold without altering specificity.^[3]^[30]^[31] CD8 exhibits specificity for non-polymorphic regions of classical MHC class I alleles, including human HLA-A, -B, and -C (e.g., Kd ≈ 145 μM for HLA-A*0201), as well as non-classical molecules like HLA-E (Kd ≈ 160 μM) and HLA-G (Kd >1000 μM), enabling broad recognition across MHC haplotypes. This selectivity excludes binding to MHC class II molecules, which lack the compatible α3 domain structure. Structural studies confirm no interaction with peptide variability, as CD8 contacts occur distal to the peptide-binding groove.^[3]^[29] Crystallographic analyses, such as the 2.7 Å structure of human CD8αα bound to HLA-A2 (PDB: 1AKJ), demonstrate that CD8 approaches the MHC class I molecule perpendicular to the peptide-binding platform, with its stalks oriented toward the T cell membrane to facilitate coreceptor positioning. Complementary nuclear magnetic resonance (NMR) data reveal conformational flexibility in the CD8 CDR loops, allowing adaptation to slight allelic variations in MHC α3 while maintaining perpendicular geometry that sterically supports TCR docking and stabilizes the immunological synapse. Murine structures (e.g., CD8αβ with H-2D^d, PDB: 3DMM) show analogous orientation, underscoring evolutionary conservation.^[29]^[30]^[32]

Downstream Signaling Pathways

Upon engagement with MHC class I molecules, the cytoplasmic tail of CD8α recruits the Src family kinase Lck through a conserved zinc finger-like motif (CxCP), positioning Lck in close proximity to the T cell receptor (TCR) complex to initiate signaling. This association enhances Lck's autophosphorylation and activation, amplifying the kinase's ability to phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 subunits of the TCR. Seminal studies have identified this Lck-binding domain as critical for CD8's co-receptor function in cytotoxic T cells. The activated Lck then phosphorylates multiple ITAMs—up to 10 per TCR complex, including three on the CD3ζ chain—creating docking sites for the dual-specificity kinase ZAP-70. ZAP-70 binds to these phosphotyrosines via its SH2 domains and becomes activated through Lck-mediated phosphorylation at tyrosine 493, leading to the phosphorylation of the adaptor protein LAT (linker for activation of T cells). Phosphorylated LAT serves as a scaffold, recruiting and activating phospholipase Cγ1 (PLCγ1), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from endoplasmic reticulum stores, initiating calcium flux that activates calcineurin and the transcription factor NFAT, while DAG activates protein kinase Cθ (PKCθ) and the RasGRP1-Ras-MAPK/ERK pathway, promoting T cell proliferation, differentiation, and cytokine production such as IL-2. CD8-mediated signaling also contributes to cytoskeletal reorganization by upregulating the affinity of the integrin LFA-1 (lymphocyte function-associated antigen 1) for its ligand ICAM-1, facilitating stable adhesion within the immunological synapse.^[33] This process involves the ADAP-SKAP55-Rap1 signaling module downstream of ZAP-70 and LAT, which converts LFA-1 from a low- to high-affinity state, enhancing T cell motility arrest and sustained signaling. To maintain signal duration and prevent excessive activation, CD8-associated pathways incorporate negative feedback through recruitment of the tyrosine phosphatase SHP-1 (Src homology 2 domain-containing phosphatase 1). SHP-1 dephosphorylates key substrates like Lck and ZAP-70, dampening ITAM signaling and limiting CD8+ T cell responsiveness to avoid autoimmunity or exhaustion.^[34] This regulatory role is particularly evident in scenarios of prolonged antigen stimulation, where SHP-1 tunes the activation threshold.^[35]

Clinical and Research Significance

Associations with Diseases

In autoimmune disorders such as type 1 diabetes (T1D), elevated numbers of autoreactive CD8+ T cells contribute to the dysregulated cytotoxic destruction of pancreatic beta cells, driving disease pathogenesis through mechanisms including single-cell RNA sequencing-identified transcriptional profiles of exhausted yet persistent effectors.^[36] Similarly, in multiple sclerosis (MS), CD8+ T cells recognizing neuron-restricted antigens infiltrate the central nervous system, injuring axons and exacerbating inflammation, with their abundance in lesions correlating to progressive disease stages.^[37] These cells often exhibit oligoclonal expansion and heightened cytotoxicity against myelin components, underscoring their role in perpetuating autoimmune demyelination.^[38] In immunodeficiencies, progressive CD8 lymphopenia, particularly of naive subsets, accompanies HIV/AIDS advancement, linking to increased susceptibility to opportunistic infections as overall CD8+ counts initially rise but functionally decline in late stages.^[39] This depletion correlates with exhausted phenotypes marked by immune checkpoint expression, predicting faster progression to AIDS-defining illnesses.^[40] Rare genetic mutations in the CD8A gene, such as the p.Gly111Ser variant, cause complete CD8+ T cell deficiency, manifesting as recurrent respiratory infections due to impaired cytotoxic surveillance without affecting T cell receptor-mediated proliferation.^[41] Another reported case highlights CD8α chain disruption leading to absent CD8+ expression and chronic sinopulmonary infections.^[42] In cancer, particularly melanoma, high densities of tumor-infiltrating CD8+ T cells serve as a favorable prognostic indicator, associating with improved patient survival through enhanced antitumor immunity in immunotherapy-naïve cases.^[43] For instance, CD103+ resident CD8+ subsets within tumors predict better melanoma-specific outcomes by localizing to the tumor microenvironment and sustaining effector functions.^[44] However, chronic antigen exposure induces CD8+ T cell exhaustion, characterized by upregulated PD-1 expression that impairs cytokine production and cytotoxicity, allowing tumor escape in advanced malignancies.^[45] Progenitor exhausted CD8+ T cells responsive to PD-1 blockade contrast with terminally exhausted populations, influencing therapeutic efficacy across solid tumors.^[46] During viral infections, persistent CD8+ T cell responses in chronic hepatitis B (HBV) and C (HCV) involve functionally impaired effectors that fail to clear virus despite initial vigorous expansion, with exhaustion driven by sustained antigen and inhibitory signals like PD-1.^[47] In HBV, these cells exhibit heterogeneous polyfunctionality but reduced antiviral potency, correlating with viral persistence and liver pathology.^[48] For COVID-19, robust early CD8+ T cell responses facilitate cytotoxic clearance of SARS-CoV-2-infected cells, associating with milder disease severity, whereas diminished or dysregulated CD8+ activity in severe cases links to prolonged viral shedding and hyperinflammation.^[49] Polyfunctional SARS-CoV-2-specific CD8+ T cells, particularly those producing interferon-γ, inversely correlate with hospitalization risk.^[50]

Therapeutic Targeting

Therapeutic strategies targeting CD8 have emerged as key components of modern immunotherapy, particularly in cancer and primary immunodeficiencies, by modulating CD8+ T cell function or directly engineering cells expressing CD8 components.^[51] Checkpoint inhibitors represent a cornerstone approach, with anti-PD-1 and anti-PD-L1 monoclonal antibodies such as pembrolizumab blocking the PD-1/PD-L1 axis to reinvigorate exhausted CD8+ T cells within the tumor microenvironment.^[52] This blockade reverses T cell dysfunction, enhancing cytotoxic activity against tumors in conditions like melanoma and non-small cell lung cancer, where clinical trials have demonstrated improved overall survival rates.^[53] For instance, pembrolizumab has shown durable responses by promoting the proliferation and effector function of intratumoral CD8+ T cells, as evidenced in phase III trials.^[54] In chimeric antigen receptor (CAR) engineering, the CD8α transmembrane domain is commonly incorporated into CAR constructs for natural killer (NK)-derived cells, alongside other elements like CD28 or CD3ζ, to anchor the receptor and support signaling.^[55] Preclinical studies of CAR-NK cells, including those derived from induced pluripotent stem cells (iPSCs), have demonstrated enhanced in vivo expansion, persistence, and tumor control in xenograft models of hematologic and solid malignancies, addressing limitations in NK cell durability.^[56]^[57] This approach is advancing toward clinical translation. Bispecific antibodies targeting peptide-MHC (pMHC) complexes and tumor antigens offer a novel means to redirect CD8+ T cells toward tumor cells by engaging the T-cell receptor (TCR) and leveraging the CD8 co-receptor, mimicking natural MHC class I antigen presentation.^[58] These molecules activate cytotoxic responses in virus-specific memory CD8+ T cells, which is useful for tumors with low MHC expression. Since the 2010s, phase I/II clinical trials have evaluated TCR-like bispecific constructs targeting MHC-presented tumor antigens, reporting objective response rates of up to 40% in refractory solid tumors with manageable cytokine release syndrome.^[59] For example, IL-2-armed pMHC bispecifics have shown potent redirection of memory CD8+ T cells in preclinical models, leading to tumor regression without broad T cell activation.^[60] More recently, as of 2024, CD8-targeted interleukin-2 (IL-2) variants have been developed to selectively expand and reinvigorate tumor-specific CD8+ T cells in human cancers, enhancing cytotoxicity while minimizing systemic toxicity associated with wild-type IL-2. Preclinical and early clinical data indicate improved antitumor immunity in solid tumors.^[61] Gene therapy approaches using lentiviral vectors to correct CD8 mutations hold promise for treating rare primary immunodeficiencies characterized by CD8+ T cell deficiencies.^[62] These vectors integrate functional CD8 genes into hematopoietic stem cells, restoring CD8 expression and T cell-mediated immunity.^[63] Preclinical studies in mouse models of CD8-related immunodeficiencies have demonstrated successful correction, with transduced cells showing normalized CD8+ T cell development and improved pathogen clearance upon challenge.^[64] Although clinical trials remain in early stages due to the rarity of CD8-specific mutations, lentiviral strategies have achieved immune reconstitution in analogous severe combined immunodeficiencies (SCIDs), providing a foundation for broader application.^[65]

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CD8 deficiency increases susceptibility to recurrent respiratory infections without interfering with the TCR-mediated proliferation of T cells.
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