CD8A

Official Full Name

CD8 subunit alpha

Organism

Homo sapiens

GeneID

925

Background

The CD8 antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell-cell interactions within the immune system. The CD8 antigen acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class I MHC molecules. The coreceptor functions as either a homodimer composed of two alpha chains or as a heterodimer composed of one alpha and one beta chain. Both alpha and beta chains share significant homology to immunoglobulin variable light chains. This gene encodes the CD8 alpha chain. Multiple transcript variants encoding different isoforms have been found for this gene. The major protein isoforms of this gene differ by the presence or absence of a transmembrane domain and thus differ in being a membrane-anchored or secreted protein. [provided by RefSeq, May 2020]

Synonyms

CD8; p32; Leu2; IMD116; CD8alpha;

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Detailed Information

The CD8A gene, located on human chromosome 2p11.2, encodes the α chain of the CD8 molecule, a core component of the CD8 transmembrane glycoprotein. CD8 is primarily expressed on cytotoxic T lymphocytes (CTLs) and certain NK cell subsets, and belongs to the immunoglobulin superfamily. Structurally, CD8 can form either a homodimer of two CD8A α chains linked by disulfide bonds or a heterodimer composed of a CD8A α chain and a CD8B β chain. The extracellular region of CD8A contains an Ig-like V-set domain, which binds specifically to the non-polymorphic α3 domain of MHC class I molecules.

Figure 1. Map of the Cd8ab gene complex. (Venkateswaran SV, et al., 2025)

Alternative splicing of CD8A produces multiple transcript variants encoding distinct isoforms. The two main isoforms differ in the presence of a transmembrane domain, resulting in either a membrane-anchored CD8 protein or a soluble extracellular form, the latter potentially playing a unique immunoregulatory role.

Biological Significance

CD8A is a critical co-receptor for T cell receptor (TCR) signaling, essential for cell-mediated adaptive immunity, particularly in the clearance of intracellular pathogens and tumor cells. When antigen-presenting cells (APCs) display endogenous peptides via MHC class I molecules, CD8+ T cells recognize the MHC I–peptide complex through the TCR, while CD8A binds the constant region of MHC I, enhancing TCR–antigen affinity and stabilizing the immune synapse. This synergy increases TCR sensitivity by several orders of magnitude.

The cytoplasmic domain of CD8A constitutively associates with the Src-family kinase LCK. Upon CD8 binding to MHC I, LCK is recruited to the TCR–CD3 complex, phosphorylating immunoreceptor tyrosine-based activation motifs (ITAMs) and initiating a downstream signaling cascade, including ZAP-70 activation, calcium mobilization, and transcription factor induction. This cascade drives clonal expansion of T cells, differentiation into fully cytotoxic effector cells, and production of key cytokines such as interferon-γ.

Beyond T cell activation, CD8 homodimers expressed on NK cells contribute to target cell recognition and serial killing, and CD8 signaling is crucial for effector-to-memory T cell differentiation and long-term survival, providing durable protective immunity. The soluble CD8A isoform, though less well-characterized, may act competitively to bind MHC I, modulating T cell activation and helping prevent excessive immune responses. Thus, CD8A serves not only as a surface marker but also as a functional hub linking antigen recognition to intracellular activation signals, determining CTL fate and efficacy.

Clinical Relevance

CD8A is a key immunological marker for diagnosis and disease stratification. Quantifying CD8+ T cell frequencies in blood or tissue by flow cytometry is standard for assessing cellular immune status in primary immunodeficiencies, acquired immunodeficiencies, and autoimmune disorders. Homozygous CD8A mutations can cause severe combined immunodeficiency, characterized by absence of CD8+ T cells, leading to heightened susceptibility to viral infections, underscoring the indispensable role of CD8A in antiviral immunity.

In tumor immunology, CD8A expression is a crucial biomarker. High densities of CD8+ CTLs in tumor tissues correlate with better prognosis and longer survival, reflecting robust antitumor immune responses. This also underpins the efficacy of immune checkpoint inhibitors (e.g., PD-1/PD-L1 blockade), which aim to reactivate exhausted CD8+ T cells in the tumor microenvironment. Monitoring CD8A expression in tumors is therefore vital for predicting immunotherapy outcomes and identifying responsive patient populations.

Therapeutically, CD8A is central to many adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, TCR-engineered T cells, and CAR-T cells, where CD8+ T cells are the primary effector population. Soluble CD8A levels in serum are also being investigated as potential biomarkers for lymphoproliferative disorders or acute rejection episodes.

References

Venkateswaran SV, Kreuzaler P, Maclachlan C, et al. A multimodal imaging pipeline to decipher cell-specific metabolic functions and tissue microenvironment dynamics. Nat Protoc. 2025 Jun;20(6):1678-1699.
Ellmeier W, Haust L, Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci. 2013 Dec;70(23):4537-53.

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