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Structures	Swiss-model
Domains	InterPro

CD8a molecule
CD8a molecule
Identifiers
Symbol	CD8A
Alt. symbols	CD8
NCBI gene	925
HGNC	1706
OMIM	186910
RefSeq	NM_001768
UniProt	P01732
Other data
Locus	Chr. 2 p12
Structures
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Structures	Swiss-model
Domains	InterPro

Putative T-cell surface glycoprotein CD8
Putative T-cell surface glycoprotein CD8
Identifiers
Symbol	CD8
Membranome	29

CD8b molecule

Identifiers

Symbol

CD8B

Alt. symbols

CD8B1

Other data

Chr. 2 p12

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Structures	Swiss-model
Domains	InterPro

CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the MHC class I protein.^[1] However, while the TCR interacts with the antigen-binding region of MHC-I, the CD8 molecule binds to the α3 domain, a non-variant region of MHC-I located away from the antigen-binding site.

There are two isoforms of the protein, alpha (CD8A) and beta (CD8B), each encoded by a different gene. In humans, both genes are located on chromosome 2 in position 2p12. CD8A is composed of 235 amino acid residues while CD8B consists of 210 residues, these two molecules share only 25 conserved residues.

Both CD8 chains are type I membrane proteins, each with three main regions: an N-terminal extracellular ectodomain (residues 23–192 in CD8A and 23–170 in CD8B), a single transmembrane helix (residues 193–219 in CD8A and 171–191 in CD8B), and a small cytoplasmic region (residues 220–235 in CD8A and 192–210 in CD8B). The ectodomain of CD8 comprises a single immunoglobulin variable (IgV)-like domain and a highly dynamic proline-rich stalk region that connects the IgV domain to the transmembrane helix.

Active form of CD8 is dimer, three different dimers have been detected CD8αα, CD8αβ, and CD8ββ^[2]

CD8 chains contain several essential cysteine residues critical for their structural and functional roles. A disulfide bond between two cysteines in the IgV domain (C45-C115 in CD8A; C41-C116 in CD8B) is a defining feature of the immunoglobulin fold, stabilizing the two beta sheets that form this domain. Additionally, C192, the last residue of the stalk region in CD8A, is critical for the dimerization, since it forms an inter-subunit disulfide bond. In CD8αα dimers, it pairs with C192 of another CD8A monomer, while in CD8αβ dimers, it pairs with C168 of CD8B.

Cysteine residues in the transmembrane helix (TMH) of CD8A also play an important role in dimerization. Studies have shown that a chimeric CD8A containing the TMH of another protein, such as the interleukin-2 receptor, exhibits a significantly reduced dimeric form.^[3]

The cytosolic portion of CD8A (but not CD8B) contains two cysteine residues, Cys215 and Cys217, which are integral to the Lck recognition site. Together with a Zn²⁺ ion and two cysteines (Cys20 and Cys23) from Lck, these residues help position the kinase near the TCR to phosphorylate the ITAM regions of CD3 subunits.

Furthermore, other cysteine residues in the cytoplasmic regions of both CD8A and CD8B can undergo palmitoylation. Palmitoylation is crucial for targeting proteins to specialized membrane regions, including lipid rafts and immunological synapses. For CD8, palmitoylation facilitates the recruitment of Lck bound to CD8 to the immunological synapse, enhancing proximity to the ITAM regions of CD3 and promoting efficient TCR signaling.

Tissue distribution

The CD8 co-receptor is predominantly expressed on the surface of cytotoxic T cells, but can also be found on natural killer cells, cortical thymocytes, and dendritic cells. The CD8 molecule is a marker for cytotoxic T cell population. It is expressed in T cell lymphoblastic lymphoma and hypo-pigmented mycosis fungoides.^[4]

Structure of the CD8 complexes

The first crystal structure of the deglycosylated IgV domain of the CD8A molecule was published by Leahy, DJ, Axel, R, and Hendrickson, WA in 1992.^[5] Since then, crystal structures have been determined for over 20 different complexes containing CD8 molecules.^[2] The extracellular immunoglobulin-like domain of CD8 monomers adopts a typical IgV fold, composed of two beta sheets (strands ABED and A'G'GFCC'C''). Hydrophobic interaction between residues at the interface of these two β-sheets together with a disulfide bond linking cysteine residues in strands B and F, create a stable domain. Loops between strands B and C (CDR1), C' and C'' (CDR2) and F and G (CDR3) mediate contact with the MHC-I. Comparison of the CD8αα and CD8αβ dimers demonstrates the overall similarity of the structure, though the dimer interface of CD8αα is a little bit larger compared with CD8αβ. Moreover, the interaction with MHC-I is very similar for CD8αα and CD8αβ. CDR loops of both subunits of CD8 dimer interact with a flexible region at the α₃ domain of an MHC-I molecule (residues 223 and 230). Importance of this interaction was confirmed by the mutational study^[6]

Function

The interaction of the extracellular IgV-like domains of CD8 with the α₃ portion of the Class I MHC molecule increases affinity for the T cell receptor of the cytotoxic T cell and the target cell such that they bound closely together during antigen-specific activation. In addition, CD8 co-receptor also plays a role in T cell signaling. The cytoplasmic tail of the CD8 co-receptor bind Lck (lymphocyte-specific protein tyrosine kinase) via common Cys₄-Zn finger. Once the T cell receptor binds its specific antigen Lck phosphorylates the cytoplasmic CD3 and ζ-chains of the TCR complex which initiates a cascade of phosphorylation eventually leading to activation of transcription factors like NFAT, NF-κB, and AP-1 which affect the expression of certain genes.^[7]

References

^ Gao G, Jakobsen B (2000). "Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor". Immunol Today. 21 (12): 630–6. doi:10.1016/S0167-5699(00)01750-3. PMID 11114424.
^ ^a ^b Srinivasan, Shreyaa; Zhu, Cheng; McShan, Andrew C. (2024-08-26). "Structure, function, and immunomodulation of the CD8 co-receptor". Frontiers in Immunology. 15. doi:10.3389/fimmu.2024.1412513. ISSN 1664-3224. PMC 11381289. PMID 39253084.
^ Hennecke, S; Cosson, P (December 1993). "Role of transmembrane domains in assembly and intracellular transport of the CD8 molecule". Journal of Biological Chemistry. 268 (35): 26607–26612. doi:10.1016/S0021-9258(19)74355-5.
^ Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. p. 73. ISBN 1-84110-100-1.
^ PDB: 1cd8; Leahy DJ, Axel R, Hendrickson WA (March 1992). "Crystal structure of a soluble form of the human T cell coreceptor CD8 at 2.6 A resolution". Cell. 68 (6): 1145–62. doi:10.1016/0092-8674(92)90085-Q. PMID 1547508. S2CID 6261613.
^ Devine L, Sun J, Barr M, Kavathas P (1999). "Orientation of the Ig domains of CD8 alpha beta relative to MHC class I". J Immunol. 162 (2): 846–51. doi:10.4049/jimmunol.162.2.846. PMID 9916707. S2CID 83819031.
^ "CD8 alpha - Marker for cytotoxic T Lymphocytes". Archived from the original on 21 September 2015. Retrieved 11 January 2016.