CD8B encodes CD8 beta, a single-pass type I transmembrane glycoprotein with an N-terminal immunoglobulin V-like domain, a glycosylated stalk, a transmembrane helix and a short cytoplasmic tail. CD8 beta does not reach the cell surface on its own; it forms a disulfide-linked heterodimer with CD8 alpha (CD8A), and the CD8 alpha-beta heterodimer is the T cell coreceptor of conventional MHC class I-restricted alpha-beta T cells and thymocytes, whereas CD8 alpha-alpha homodimers are found on intestinal intraepithelial T cells, gamma-delta T cells and NK cells. On the T cell, CD8 alpha-beta binds the alpha3 domain of MHC class I on the antigen-presenting cell at the same time as the T cell receptor (TCR) binds the peptide-MHC complex; in the mouse crystal structure the beta subunit contributes about half of the buried interface and sits in the T cell membrane-proximal position. CD8 alpha-beta is a much stronger coreceptor than CD8 alpha-alpha. The kinase LCK is bound by the CxC zinc-clasp motif of the CD8 alpha tail, not by CD8 beta; the CD8 beta tail instead carries a membrane-proximal palmitoylation site that partitions the heterodimer into plasma membrane lipid rafts, where LCK is enriched, and it promotes association of CD8 with TCR-CD3. Together these increase the avidity of TCR for peptide-MHC class I, the recruitment of active LCK to the engaged receptor, and phosphorylation of CD3 ITAMs, which lowers the antigen threshold for T cell activation. In mice, loss of CD8 beta or of its cytoplasmic domain reduces CD8 alpha-associated LCK activity and impairs development of CD8 single-positive thymocytes. Alternative splicing produces several isoforms that differ in the cytoplasmic tail, and some lack the transmembrane segment and are predicted to be secreted. Of the four human membrane isoforms (M-1 to M-4), M-1, the equivalent of mouse CD8 beta, predominates in naive T cells and M-4, whose longer tail carries a leucine-based internalization motif, predominates in effector memory T cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002250 adaptive immune response | NAS PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | KEEP AS NON CORE | Summary: CD8 alpha-beta is the MHC class I coreceptor of conventional alpha-beta T cells, so CD8B acts in the adaptive immune response. Reason: Correct but very broad. The specific processes CD8B takes part in are T cell receptor signaling (GO:0050852) and T cell activation (GO:0042110), which are kept as core. Kept as a high-level non-core process, as for the CD3 chains in this project. Supporting Evidence: PMID:17145893 CD8 acts to stabilize the binding of the T-cell receptor (TCR) to the peptide-MHC complex while localizing p56(lck) (lck) to the TCR/CD3 complex to facilitate early signaling events. |
| GO:0005515 protein binding | IPI PMID:2493728 Molecular biology and function of CD4 and CD8. | REMOVE | Summary: Generic protein binding with CD8A, cited to a 1989 review of CD4 and CD8 (no abstract in the cache). Reason: Generic protein binding is uninformative. The partner, CD8A, is CD8 beta's obligate heterodimer partner; that relationship is already shown by the requirement of CD8A for CD8B surface expression and is better captured by coreceptor activity and MHC class I binding for the heterodimer than by a binding row. The source is a review, not a primary interaction experiment. This matches the removal of the reciprocal row on CD8A (genes/human/CD8A). Supporting Evidence: PMID:3145196 Interestingly, the human Lyt-3 molecule cannot be expressed alone, but requires the human Lyt-2 homologue for efficient cell surface expression. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mapped from the UniProt "Secreted" location given to the splice isoforms that lack the transmembrane segment (isoforms 3, 6, 7, 8). Reason: A transcript lacking the transmembrane exon was found in the original cloning and is predicted to encode a secreted protein; secretion has not been shown and the function of soluble CD8 beta is unknown. The functional form is membrane-bound, so this is kept as non-core and isoform-specific. Supporting Evidence: PMID:3145195 One of the cDNAs lacks nucleotide sequences corresponding to a hydrophobic transmembrane domain, and may encode a secreted CD8 beta protein. |
| GO:0005886 plasma membrane | EXP PMID:11714755 CD8beta endows CD8 with efficient coreceptor function by cou... | ACCEPT | Summary: CD8 alpha-beta on the T cell surface, partitioned into lipid rafts by the CD8 beta tail. Reason: CD8 beta functions at the T cell plasma membrane as part of the CD8 alpha-beta coreceptor. The experiments use transfected T cell hybridomas (mouse system); the location is conserved and also shown for human CD8B in PMID:3145195 and PMID:3145196. Supporting Evidence: PMID:11714755 Here we report that cell-associated CD8alphabeta, but not CD8alphaalpha or soluble CD8alphabeta, substantially increases the avidity of T cell receptor (TCR)-ligand binding. |
| GO:0005886 plasma membrane | EXP PMID:3145196 The human Lyt-3 molecule requires CD8 for cell surface expre... | ACCEPT | Summary: Human CD8 beta (Lyt-3) reaches the cell surface only when coexpressed with CD8 alpha. Reason: Transfection study of the cloned human cDNA showing surface expression dependent on CD8A. Supporting Evidence: PMID:3145196 Interestingly, the human Lyt-3 molecule cannot be expressed alone, but requires the human Lyt-2 homologue for efficient cell surface expression. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence places CD8B at the plasma membrane. Reason: Consistent with the primary literature on surface CD8 alpha-beta. Supporting Evidence: PMID:3145195 About 90% of human CD8 alpha positive thymocytes and peripheral blood lymphocytes express CD8 beta at the cell surface. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated plasma membrane annotation for a type I transmembrane glycoprotein. Reason: Correct; supported by experimental data on human CD8 beta. Supporting Evidence: PMID:3145195 show that the CD8 beta protein is expressed on the surface of CD8+ human T cells |
| GO:0005886 plasma membrane | TAS PMID:3145195 A second subunit of CD8 is expressed in human T cells. | ACCEPT | Summary: The cloning paper for human CD8B shows CD8 beta on the surface of human CD8+ T cells. Reason: Direct statement of surface expression of human CD8 beta on thymocytes and blood T cells. Supporting Evidence: PMID:3145195 About 90% of human CD8 alpha positive thymocytes and peripheral blood lymphocytes express CD8 beta at the cell surface. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-182186 | ACCEPT | Summary: Reactome places CD8 alpha-beta at the plasma membrane before HIV Nef-induced internalization. Reason: Correct location; the Nef context does not change the native location of the protein. Supporting Evidence: Reactome:R-HSA-182186 The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD8. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-182198 | ACCEPT | Summary: Reactome internalization reaction starting from surface CD8 alpha-beta. Reason: Correct location of the receptor before endocytosis. Supporting Evidence: Reactome:R-HSA-182198 The CD8alphabeta receptor is internalized via endocytosis. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-198955 | ACCEPT | Summary: Reactome reaction in which TCR, CD3 and CD8 at the T cell surface engage peptide-MHC class I. Reason: Correct location; this is the functional setting of CD8 beta. Supporting Evidence: Reactome:R-HSA-198955 This particular reaction depicts the interaction of the TCR with MHC Class I molecules on somatic cell, requiring the support of CD3 and CD8 proteins. |
| GO:0006955 immune response | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | KEEP AS NON CORE | Summary: Very broad process term from a paper on pharmacological down-regulation of CD8 alpha (abstract only). Reason: True for CD8 beta as part of the CD8 coreceptor, but uninformative; T cell receptor signaling and T cell activation are the specific core processes. The cited paper is about CD8 alpha expression and only states the general coreceptor role of CD8. Supporting Evidence: PMID:11131152 The CD8 glycoprotein serves as a coreceptor for T cell receptor (TCR)-mediated recognition of peptides associated to MHC class I. |
| 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: Statement-based annotation from a paper on zinc-dependent binding of LCK to CD4 and CD8 alpha. Reason: GO:0007169 is defined for pathways in which the receptor itself has tyrosine kinase activity. Neither the TCR nor CD8 has kinase activity; 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. The cited paper also concerns the CD8 alpha tail, which binds LCK; CD8 beta does not. The intended process is T cell receptor signaling pathway. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:9830036 Binding of the protein tyrosine kinase p56(lck) to T-cell co-receptors CD4 and CD8alpha is necessary for T-lymphocyte development and activation. file:human/CD8B/CD8B-deep-research-falcon.md Describing CD8Ξ² itself as the LCK-binding catalytic signaling chain would misassign both the binding site and enzymatic activity. |
| GO:0015026 coreceptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the CD8 beta family entry. Reason: Coreceptor activity is the defining activity of CD8 alpha-beta, and CD8 beta is the subunit that makes CD8 an efficient coreceptor. Supporting Evidence: PMID:11714755 While several studies have shown that the CD8beta chain endows CD8 with efficient coreceptor function, the molecular basis for this is enigmatic. |
| GO:0015026 coreceptor activity | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: CD8 is the MHC class I coreceptor for TCR recognition. Reason: Core molecular function. Experimental support for CD8 beta's contribution comes from Arcaro et al. (palmitoylation, raft partitioning, TCR/CD3 coupling) and from the CD8alpha-beta/MHC class I structure, in which CD8 beta forms about half of the MHC contact surface. Supporting Evidence: PMID:11131152 The CD8 glycoprotein serves as a coreceptor for T cell receptor (TCR)-mediated recognition of peptides associated to MHC class I. PMID:10925291 This study shows that palmitoylation of CD8beta is required for efficient CD8 coreceptor function, mainly because it dramatically increases CD8 association with p56lck and CD8-mediated activation of p56lck in lipid rafts. PMID:23738014 We demonstrate that the co-transduced CD8Ξ±Ξ² co-receptor in HLA-I-TCR transduced CD4(+) T-cells behaves as an adhesion molecule, since for optimal antigen-specific HLA class I restricted CD4(+) T-cell reactivity the extracellular domains of the CD8Ξ± and Γ subunits are sufficient. |
| GO:0031901 early endosome membrane | TAS Reactome:R-HSA-182171 | KEEP AS NON CORE | Summary: Reactome places internalized CD8 alpha-beta in early endosomes on the way to lysosomal degradation, in the HIV Nef down-modulation pathway. Reason: Plausible transient location of the receptor after endocytosis (accelerated by HIV Nef), not where CD8 beta works. Kept as non-core. Supporting Evidence: Reactome:R-HSA-182171 Once the CD8alphabeta receptor has been internalized via endocytosis, the vesicles are targeted for lysosomal degradation. |
| GO:0031901 early endosome membrane | TAS Reactome:R-HSA-182198 | KEEP AS NON CORE | Summary: Reactome internalization of CD8 alpha-beta with Nef and AP-2 into endosomes. Reason: Same as the other Reactome early endosome row; a trafficking location, non-core. Supporting Evidence: Reactome:R-HSA-182198 The CD8alphabeta receptor is internalized via endocytosis. |
| 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: Statement that CD8 beta is part of the T cell receptor complex, cited to a CD8 alpha expression paper (abstract only). Reason: GO defines the T cell receptor complex as the TCR heterodimer associated with the CD3 chains; CD8 is a coreceptor, not a subunit. The CD8 beta tail does promote association of CD8 alpha-beta with TCR/CD3, so CD8 and the TCR form adducts at the synapse, but this is a coreceptor-receptor interaction, not complex membership, and the cited abstract makes no such claim. The CD8A review accepted the matching row; this review takes the stricter reading of the term definition. Supporting Evidence: PMID:11714755 In addition, the cytoplasmic portion of CD8beta mediates constitutive association of CD8 with TCR/CD3. |
| GO:0042110 T cell activation | IDA PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | ACCEPT | Summary: Reconstitution of full-length and truncated CD8 alpha and CD8 beta in CD8-negative Jurkat cells expressing defined TCRs enhanced antigen-induced T cell activation (abstract only). Reason: CD8 alpha-beta takes part in TCR-triggered activation by binding MHC class I and bringing LCK to the receptor; the experiment measures antigen-specific activation directly. Accepted; T cell receptor signaling pathway is the more specific core process. Supporting Evidence: PMID:17145893 We have addressed these issues by introducing full-length and truncated versions of the CD8alpha and CD8beta chains into CD8(-) Jurkat cell clones expressing cloned TCRs with known antigen specificity and relative affinities. |
| GO:0042110 T cell activation | NAS PMID:9830036 Zinc is essential for binding of p56(lck) to CD4 and CD8alph... | ACCEPT | Summary: Statement-based T cell activation annotation from a paper on LCK binding to CD4 and CD8 alpha. Reason: The process is correct for CD8 alpha-beta, as supported by the IDA row from PMID:17145893 and by Arcaro et al.; the cited paper itself concerns the CD8 alpha tail. Supporting Evidence: PMID:11714755 Engagement of these TCR/CD3-CD8/lck adducts by multimeric MHC-peptide induces activation of p56(lck) in rafts, which in turn phosphorylates CD3 and initiates T cell activation. |
| GO:0042288 MHC class I protein binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping for MHC class I binding by the CD8 beta family. Reason: In the CD8alpha-beta/H-2Dd structure the CD8 beta subunit contributes about half of the buried surface on the MHC class I alpha3 domain, so CD8 beta binds MHC class I directly as part of the heterodimer. Supporting Evidence: PMID:19625641 The CD8Ξ² subunit of CD8Ξ±Ξ² contributes almost equally (49%) to the buried surface of the interface. |
| GO:0042288 MHC class I protein binding | NAS PMID:11131152 Calyculin A inhibits expression of CD8alpha but not CD4 in h... | ACCEPT | Summary: CD8 binds MHC class I as the coreceptor of the TCR. Reason: Correct and core; supported structurally for the CD8 alpha-beta heterodimer (mouse) by PMID:19625641. Supporting Evidence: PMID:19625641 The focus of the CD8alphabeta interaction is the acidic loop (residues 222-228) of the alpha3 domain of H-2D(d). PMID:16356863 mutations in CD8beta CDR2 and CDR3 loops abolish CD8alphabeta coreceptor activity |
| GO:0050776 regulation of immune response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to a broad regulatory process. Reason: T cell receptor signaling pathway is a descendant of this term; the broad parent adds nothing beyond the specific core process. Kept as non-core. Supporting Evidence: PMID:17145893 we find that the intracellular lck-binding domain of CD8 is critical for enhanced T-cell activation regardless of the relative strength of the TCR. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:17145893 Influence of human CD8 on antigen recognition by T-cell rece... | ACCEPT | Summary: CD8 alpha-beta reconstitution in Jurkat cells enhances TCR-triggered signaling and activation (abstract only). Reason: Core process. CD8 beta contributes to TCR signaling by raising TCR avidity for peptide-MHC class I and by partitioning CD8 and the engaged TCR into rafts where LCK is activated and phosphorylates CD3. Supporting Evidence: PMID:17145893 CD8 acts to stabilize the binding of the T-cell receptor (TCR) to the peptide-MHC complex while localizing p56(lck) (lck) to the TCR/CD3 complex to facilitate early signaling events. PMID:11714755 Engagement of these TCR/CD3-CD8/lck adducts by multimeric MHC-peptide induces activation of p56(lck) in rafts, which in turn phosphorylates CD3 and initiates T cell activation. |
| GO:0044853 plasma membrane raft | ISS PMID:10925291 Essential role of CD8 palmitoylation in CD8 coreceptor funct... | NEW | Summary: The palmitoylated CD8 beta tail partitions CD8 alpha-beta into plasma membrane lipid rafts. Reason: Raft partitioning is the best-characterized activity of the CD8 beta tail. It was shown in T cell hybridomas (mouse system) by Cys-to-Ala mutation and tail deletion of CD8 beta; the human CD8 beta tail keeps a membrane-proximal cysteine pair (HLCCRRRR). UniProt states the same for human CD8B. CD8A already carries plasma membrane raft (IDA) in GOA. Supporting Evidence: PMID:10925291 We demonstrate that CD8 is palmitoylated at the cytoplasmic tail of CD8beta and that this allows partitioning of CD8alphabeta, but not of CD8alphaalpha, in lipid rafts. PMID:11714755 Thus, mutation of Cys179 of CD8Ξ² impaired CD8 association with rafts as dramatically as deletion of the CD8Ξ² tail. |
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Download this section (compressed HTML)Q: Should CD8 alpha-beta coreceptors be annotated part_of T cell receptor complex (GO:0042101), given that the term definition lists only the TCR heterodimer and CD3 chains, while CD8 beta promotes constitutive association of CD8 with TCR/CD3? The CD8A and CD8B reviews currently treat this row differently.
Q: Is a GO cellular component for the CD8 alpha-beta heterodimer (analogous to existing receptor complex terms) wanted, so that the obligate CD8A-CD8B pairing can be recorded without generic protein binding rows?
Q: Do the secreted CD8 beta splice isoforms (lacking the transmembrane exon) produce a soluble protein in vivo, and does it have any function?
Experiment: Express human CD8B with the membrane-proximal cysteines mutated (C to A) together with CD8A in CD8-negative human T cells carrying a defined MHC class I-restricted TCR, and measure raft partitioning, CD8-LCK association, TCR-pMHC avidity and antigen sensitivity, to test whether the mouse palmitoylation mechanism holds for human CD8 beta.
Experiment: Determine the structure of human CD8 alpha-beta bound to HLA class I, and test CD8B CDR-like loop mutants for MHC class I tetramer binding, to define the human CD8 beta contact surface.
Experiment: Detect soluble CD8 beta isoforms in plasma or T cell culture supernatant with isoform-specific antibodies or targeted mass spectrometry.
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