CD8A encodes the alpha subunit of the CD8 glycoprotein, a type I transmembrane co-receptor expressed on cytotoxic T lymphocytes that plays a central role in adaptive immunity. CD8 exists as homodimers (CD8aa) or heterodimers with CD8 beta (CD8ab), with heterodimers showing approximately 100-fold greater co-receptor activity. The extracellular immunoglobulin-like domain binds the alpha-3 domain of MHC class I molecules, while the cytoplasmic tail contains a zinc clasp motif (Cys215/217) that coordinates with Lck kinase (Cys20/23), positioning the kinase for phosphorylation of CD3 ITAMs to initiate T cell receptor signaling. CD8ab heterodimers localize preferentially to lipid rafts through palmitoylation, enhancing signal transduction. CD8 enhances T cell sensitivity to weak TCR-peptide-MHC interactions through affinity enhancement and catch-bond mechanics, lowering activation thresholds. Essential for positive selection of CD8+ thymocytes and cytotoxic T cell function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Cell surface receptor signaling - CD8 participates in T cell receptor signaling at the cell surface by recruiting Lck kinase. Reason: Correct general term. CD8 functions as a co-receptor that enhances cell surface TCR signaling by recruiting Lck kinase to phosphorylate CD3 ITAMs. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The primary molecular function of CD8 in the context of T cell activation involves the recruitment and positioning of the Lck tyrosine kinase to the T cell receptor complex file:human/CD8A/CD8A-deep-research-falcon.md See deep research file for comprehensive analysis |
| GO:0002456 T cell mediated immunity | IBA GO_REF:0000033 | ACCEPT | Summary: T cell mediated immunity - CD8+ cytotoxic T lymphocytes are central to cell-mediated immunity against intracellular pathogens. Reason: Core biological process. CD8 is the defining marker of cytotoxic T lymphocytes that mediate cell-mediated immunity against virus-infected and tumor cells. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The CD8A gene encodes the alpha subunit of the CD8 glycoprotein, a transmembrane co-receptor expressed on the surface of cytotoxic T lymphocytes that plays a central role in adaptive immunity and immune surveillance |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: External side of plasma membrane - CD8 IgV domain is exposed on the external cell surface for MHC class I binding. Reason: Correct and specific localization. The extracellular IgV-like domain of CD8 extends from the plasma membrane to engage MHC class I molecules on target cells. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The extracellular portion of CD8A extends from amino acids 23 to 182, comprising an immunoglobulin variable-like domain (IgV-like domain) that directly contacts major histocompatibility complex class I molecules |
| GO:0045065 cytotoxic T cell differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Cytotoxic T cell differentiation - CD8 is required for positive selection and development of CD8+ cytotoxic T cells. Reason: Core developmental process. CD8 expression is essential for positive selection of CD8+ thymocytes and commitment to the cytotoxic T cell lineage. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The requirement for CD8 in this critical developmental decision appears to extend beyond its function as a signaling molecule |
| GO:0002250 adaptive immune response | IEA GO_REF:0000043 | ACCEPT | Summary: Adaptive immune response - CD8+ T cells are a key effector arm of adaptive immunity. Reason: Correct high-level process. CD8+ cytotoxic T lymphocytes are essential components of adaptive immune responses against intracellular pathogens and tumors. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8A encodes the alpha subunit of the CD8 glycoprotein, a transmembrane co-receptor expressed on the surface of cytotoxic T lymphocytes that plays a central role in adaptive immunity |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: Immune system process - very general parent term for immune functions. Reason: Correct but very general. CD8 is central to immune function. More specific child terms are also annotated. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8A encodes a molecule of remarkable functional sophistication that has evolved to serve as a critical hub for integrating multiple dimensions of immune recognition and signaling |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Extracellular region - soluble CD8a isoform can be secreted. Reason: Partially correct. An alternatively spliced mRNA encodes a secreted form of human CD8 alpha. However, the primary form is membrane-bound. This is a non-core function. Supporting Evidence: PMID:2496167 Alternatively spliced mRNA encodes a secreted form of human CD8 alpha |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization - CD8 is a type I transmembrane protein on the T cell surface. Reason: Core cellular component. CD8 is a type I transmembrane glycoprotein anchored to the plasma membrane. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The CD8 alpha chain, like its beta chain counterpart, is organized as a type I transmembrane protein |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Cell surface receptor signaling pathway - duplicate with IBA annotation. Reason: Correct annotation with different evidence code (ARBA machine learning). CD8 participates in TCR signaling at the cell surface. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8 contributes to the first signal by stabilizing low-affinity TCR interactions with peptide-MHC complexes and enhancing their recognition |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: External side of plasma membrane - duplicate with IBA annotation. Reason: Correct localization with different evidence code. The IgV-like domain is exposed extracellularly. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The extracellular portion of CD8A extends from amino acids 23 to 182 |
| GO:0042110 T cell activation | IEA GO_REF:0000117 | ACCEPT | Summary: T cell activation - CD8 is essential for optimal activation of CD8+ T cells. Reason: Core biological process. CD8 co-receptor function enhances T cell activation by recruiting Lck kinase and stabilizing TCR-pMHC interactions. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The initial activation of naive CD8+ T cells occurs when dendritic cells presenting processable antigens are encountered |
| GO:0043235 receptor complex | IEA GO_REF:0000117 | ACCEPT | Summary: Receptor complex - CD8 forms part of the T cell receptor complex. Reason: Correct. CD8 associates with the TCR complex and functions as a co-receptor, forming trimolecular complexes with TCR and pMHC. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The formation of catch bonds requires functional TCR-CD8-MHC trimolecular complexes |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane from immunofluorescence curation. Reason: Correct localization supported by immunofluorescence evidence. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8 alpha chain is organized as a type I transmembrane protein |
| GO:0002250 adaptive immune response | NAS PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | ACCEPT | Summary: Adaptive immune response from study of CD8 influence on antigen recognition. Reason: Correct. PMID:17145893 examined CD8 influence on T cell receptor-mediated antigen recognition in adoptive T cell therapy. Supporting Evidence: PMID:17145893 Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells |
| GO:0002250 adaptive immune response | NAS PMID:22081144 CD8Ξ±Ξ± and -Ξ±Ξ² isotypes are equally recruited to the immunolo... | ACCEPT | Summary: Adaptive immune response from study of CD8 isotypes at the immunological synapse. Reason: Correct. PMID:22081144 demonstrated that CD8aa and CD8ab are both recruited to the immunological synapse through MHC class I binding. Supporting Evidence: PMID:22081144 CD8Ξ±Ξ± and -Ξ±Ξ² isotypes are equally recruited to the immunological synapse through their ability to bind to MHC class I |
| GO:0005886 plasma membrane | ISO GO_REF:0000114 | ACCEPT | Summary: Plasma membrane from homologous complex annotation. Reason: Correct localization inferred from sequence similarity to characterized orthologs. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md type I transmembrane protein |
| GO:0042110 T cell activation | ISS GO_REF:0000114 | ACCEPT | Summary: T cell activation from sequence similarity to characterized orthologs. Reason: Correct. CD8 function in T cell activation is highly conserved across species. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8 co-receptor function enhances T cell activation |
| GO:0042110 T cell activation | IDA PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | ACCEPT | Summary: T cell activation from direct experimental evidence showing CD8 enhances T cell responses. Reason: Core function demonstrated experimentally. PMID:17145893 showed CD8 influences antigen recognition and T cell activation. Supporting Evidence: PMID:17145893 Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells |
| GO:0043235 receptor complex | ISO GO_REF:0000114 | ACCEPT | Summary: Receptor complex from homologous complex annotation. Reason: Correct. CD8 forms receptor complexes conserved across species. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md trimolecular complexes |
| GO:0043235 receptor complex | IPI PMID:17243170 Computational design and crystal structure of an enhanced af... | ACCEPT | Summary: Receptor complex from crystal structure of enhanced affinity CD8aa mutant. Reason: Correct. PMID:17243170 provided structural evidence for CD8aa homodimer complex formation. Supporting Evidence: PMID:17243170 Computational design and crystal structure of an enhanced affinity mutant human CD8 alphaalpha coreceptor |
| GO:0050852 T cell receptor signaling pathway | ISS GO_REF:0000114 | ACCEPT | Summary: T cell receptor signaling pathway - CD8 is essential for efficient TCR signaling by recruiting Lck kinase. Reason: Core function. CD8 recruits Lck to phosphorylate CD3 ITAMs, initiating the TCR signaling cascade. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The primary molecular function of CD8 in the context of T cell activation involves the recruitment and positioning of the Lck tyrosine kinase to the T cell receptor complex |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | ACCEPT | Summary: T cell receptor signaling pathway from direct experimental evidence. Reason: Core function demonstrated experimentally. Supporting Evidence: PMID:17145893 Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells |
| GO:0005515 protein binding | IPI PMID:9177355 Crystal structure of the complex between human CD8alpha(alph... | MODIFY | Summary: Protein binding from CD8aa-HLA-A2 crystal structure study. Reason: The generic "protein binding" is uninformative. The specific interaction demonstrated was MHC class I binding, which is already captured by GO:0023024. This crystal structure paper showed CD8aa binding to HLA-A2. Proposed replacements: MHC class I protein complex binding Supporting Evidence: PMID:9177355 Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2 |
| GO:0005886 plasma membrane | IDA PMID:2784196 Polymorphism in the alpha 3 domain of HLA-A molecules affect... | ACCEPT | Summary: Plasma membrane from HLA-CD8 binding study. Reason: Correct. Study demonstrated cell surface interactions between CD8 and MHC class I. Supporting Evidence: PMID:2784196 Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8 |
| GO:0023024 MHC class I protein complex binding | IDA PMID:2784196 Polymorphism in the alpha 3 domain of HLA-A molecules affect... | ACCEPT | Summary: MHC class I protein complex binding - core molecular function of CD8. Reason: Core molecular function. CD8 IgV-like domain binds the alpha-3 domain of MHC class I molecules. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The IgV-like domain itself is stabilized by a conserved disulfide bond between cysteine residues at positions 43 and 115 in CD8A, a structural feature characteristic of the immunoglobulin fold and essential for maintaining the domain's structural integrity and binding capability PMID:2784196 Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8 |
| GO:0023024 MHC class I protein complex binding | IDA PMID:9177355 Crystal structure of the complex between human CD8alpha(alph... | ACCEPT | Summary: MHC class I protein complex binding from CD8aa-HLA-A2 crystal structure. Reason: Core molecular function demonstrated structurally. Crystal structure showed precise molecular basis of CD8-MHC class I binding. Supporting Evidence: PMID:9177355 Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2 |
| GO:0005515 protein binding | IPI PMID:12853576 Human inhibitory receptors Ig-like transcript 2 (ILT2) and I... | REMOVE | Summary: Protein binding from study of ILT2/ILT4 competition with CD8 for MHC binding. Reason: Generic "protein binding" is uninformative per curation guidelines. The specific interaction (competition for MHC binding) is better captured by MHC class I binding terms already annotated. Supporting Evidence: PMID:12853576 Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. |
| GO:0044853 plasma membrane raft | IDA PMID:17341584 CD8 Raft localization is induced by its assembly into CD8alp... | ACCEPT | Summary: Plasma membrane raft (lipid raft) localization - CD8ab heterodimers localize to lipid rafts through palmitoylation. Reason: Important localization for CD8 function. CD8ab heterodimers localize to lipid rafts, which enhances Lck recruitment and signaling efficiency. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8 beta chain palmitoylation at these sites is necessary for efficient CD8ab heterodimer localization to rafts, a feature that may account for the superior co-receptor function of CD8ab compared to CD8aa PMID:17341584 CD8 Raft localization is induced by its assembly into CD8alpha beta heterodimers, Not CD8alpha alpha homodimers |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-198955 | ACCEPT | Summary: Plasma membrane from Reactome pathway on TCR-MHC class I interaction. Reason: Correct. Reactome pathway documents CD8 at plasma membrane during TCR-MHC interaction. Supporting Evidence: Reactome:R-HSA-198955 TCR complex interacts with peptide antigen-presenting MHC Class I |
| GO:0009897 external side of plasma membrane | IDA PMID:17213291 FcRL6, a new ITIM-bearing receptor on cytolytic cells, is br... | ACCEPT | Summary: External side of plasma membrane from FcRL6 expression study. Reason: Correct localization. CD8 is exposed on the external cell surface. Supporting Evidence: PMID:17213291 FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly expressed by lymphocytes following HIV-1 infection |
| GO:0005515 protein binding | IPI PMID:2470098 The CD4 and CD8 antigens are coupled to a protein-tyrosine k... | MODIFY | Summary: Protein binding from study showing CD8 couples to Lck kinase. Reason: Generic "protein binding" is uninformative. This study specifically demonstrated CD8 binding to Lck (p56lck) through a zinc-coordinated interaction. A more specific term should be used. Proposed replacements: non-membrane spanning protein tyrosine kinase activity Supporting Evidence: PMID:2470098 The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex |
| GO:0005886 plasma membrane | NAS PMID:2496167 Alternatively spliced mRNA encodes a secreted form of human ... | ACCEPT | Summary: Plasma membrane from CD8 alpha gene characterization study. Reason: Correct. Study characterized CD8A gene and identified membrane-bound form. Supporting Evidence: PMID:2496167 Alternatively spliced mRNA encodes a secreted form of human CD8 alpha |
| GO:0019882 antigen processing and presentation | NAS PMID:2496167 Alternatively spliced mRNA encodes a secreted form of human ... | KEEP AS NON CORE | Summary: Antigen processing and presentation from CD8A gene study. Reason: CD8 is involved in the presentation/recognition side but not antigen processing per se. CD8 enhances recognition of MHC-peptide complexes. This is a non-core peripheral annotation. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md This spatial segregation of binding sites is functionally crucial, as it allows the TCR and CD8 to cooperatively enhance recognition and activation PMID:2496167 Alternatively spliced mRNA encodes a secreted form of human CD8 alpha. |
| GO:0005515 protein binding | IPI PMID:2493728 Molecular biology and function of CD4 and CD8. | REMOVE | Summary: Protein binding from molecular biology review of CD4 and CD8. Reason: Generic "protein binding" is uninformative per curation guidelines. The review discusses specific interactions (MHC class I, Lck) that are captured by other more specific terms. Supporting Evidence: PMID:2493728 Molecular biology and function of CD4 and CD8. |
| GO:0006955 immune response | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: Immune response - general term for CD8+ T cell function. Reason: Correct general term. CD8+ T cells mount immune responses against infected and transformed cells. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md CD8A encodes a molecule of remarkable functional sophistication that has evolved to serve as a critical hub for integrating multiple dimensions of immune recognition PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in human peripheral blood T cells. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | NAS PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alph... | ACCEPT | Summary: Receptor protein tyrosine kinase signaling - CD8 recruits Lck kinase for TCR signaling. Reason: Correct. CD8 recruits the Lck protein tyrosine kinase to the TCR complex for signal transduction. Supporting Evidence: PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alpha |
| GO:0015026 coreceptor activity | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: Coreceptor activity - core molecular function of CD8. Reason: Core molecular function. CD8 is the defining coreceptor for MHC class I-restricted T cell responses. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md The fundamental function of CD8A as a co-receptor depends on its ability to engage major histocompatibility complex class I molecules PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in human peripheral blood T cells. |
| GO:0042101 T cell receptor complex | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: T cell receptor complex - CD8 associates with TCR complex during signaling. Reason: Correct. CD8 forms trimolecular complexes with TCR and peptide-MHC during T cell activation. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md trimolecular complexes PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in human peripheral blood T cells. |
| GO:0042110 T cell activation | NAS PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alph... | ACCEPT | Summary: T cell activation from zinc-Lck binding study. Reason: Correct. Study showed zinc is essential for CD8-Lck binding which is required for T cell activation. Supporting Evidence: PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alpha |
| GO:0042288 MHC class I protein binding | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: MHC class I protein binding - core molecular function of CD8. Reason: Core molecular function. CD8 binds the alpha-3 domain of MHC class I molecules. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md Crystal structures of CD8-MHC class I complexes have demonstrated that the IgV-like domain of CD8A contacts the alpha-3 domain of MHC class I PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in human peripheral blood T cells. |
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