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 |
| 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... | MODIFY | Summary: Receptor protein tyrosine kinase signaling - CD8 recruits Lck kinase for TCR signaling. Reason: GO:0007169 is defined for pathways in which the receptor itself has tyrosine kinase activity. Neither the TCR nor CD8 does; they signal through the associated Src-family kinase LCK, and GO places T cell receptor signaling pathway (GO:0050852) under antigen receptor-mediated signaling, not under GO:0007169. Harmonised with the CD8B review of the same NAS row. Proposed replacements: T cell receptor signaling pathway 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 |
| GO:0042101 T cell receptor complex | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | MARK AS OVER ANNOTATED | Summary: T cell receptor complex - CD8 associates with TCR complex during signaling. Reason: CD8 is a coreceptor that joins TCR and peptide-MHC transiently during engagement; it is not a subunit of the TCR complex as GO defines it (TCR heterodimer plus CD3 chains). The cited NAS paper concerns CD8alpha expression, not complex membership. Harmonised with the CD4 and CD8B reviews, which mark the same row over-annotated. Supporting Evidence: file:human/CD8A/CD8A-deep-research-perplexity.md trimolecular complexes |
| 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 |
| GO:1990782 protein tyrosine kinase binding | IDA PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alph... | NEW | Summary: Proposed annotation for the CD8alpha cytoplasmic tail binding the Src-family kinase LCK through a zinc clasp. Reason: The CD8alpha tail CxC motif and the LCK N-terminal cysteines coordinate a zinc ion, and in vitro binding requires Zn2+. This is the CD8alpha counterpart of the CD4-LCK interaction annotated as GO:1990782 in the CD4 review, and the reverse of GO:0042610 CD8 receptor binding on LCK. CD8beta does not carry the motif. Supporting Evidence: PMID:9830036 In an in vitro binding reaction, Zn2+ mediates p56(lck) association with a glutathione S-transferase (GST) fusion protein containing the cytosolic domains of CD4 or CD8alpha |
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