Glycosylation and the Function of the T Cell Co-Receptor CD8

Shore, D.A.; Wilson, Ian A.; Dwek, Raymond A.; Rudd, Pauline M.

doi:10.1007/0-387-25515-x_12

Cited by 7 publications

(7 citation statements)

References 59 publications

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“…Biophysical studies of mucins have shown that O-glycans stiffen polypeptides through steric interactions between peptide-linked N-acetylgalactosamine residues and adjacent peptide residues (40,41). Similarly, O-glycans in the CD8 stalk polypeptides were found to reduce the overall extension of the stalk from a theoretical maximum of 3.4 Å per residue to 2.6 Å per residue, suggesting rigidification (39,42). Hence, O-glycosylation may limit the mobility of the CD8 head group that binds MHC class I, thereby imposing constraints on the orientation of CD3 relative to CD8-bound Lck, as in the TCR-pMHC-CD4 complex.…”

Section: Dimerization (Or Oligomerization) Of Cd4 (15) Mhc (18) or mentioning

confidence: 99%

“…Although the TCR-pMHC-CD8 complex is probably not as conformationally constrained as the TCR-pMHC-CD4 complex, there is evidence that the CD8 stalk may not be as flexible as generally believed, because of O-glycosylation at multiple sites in CD8α and CD8β (39). Biophysical studies of mucins have shown that O-glycans stiffen polypeptides through steric interactions between peptide-linked N-acetylgalactosamine residues and adjacent peptide residues (40,41).…”

Section: Dimerization (Or Oligomerization) Of Cd4 (15) Mhc (18) or mentioning

confidence: 99%

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Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4

Yin

Wang

Mariuzza

2012

Proc. Natl. Acad. Sci. U.S.A.

117

138

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Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65°relative to the Tcell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.

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Section: Dimerization (Or Oligomerization) Of Cd4 (15) Mhc (18) or mentioning

confidence: 99%

Section: Dimerization (Or Oligomerization) Of Cd4 (15) Mhc (18) or mentioning

confidence: 99%

Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4

Yin

Wang

Mariuzza

2012

Proc. Natl. Acad. Sci. U.S.A.

117

138

View full text Add to dashboard Cite

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“…It has been proven that CD8 and TCR cooperatively bind pMHC-I and enhance peptide discrimination (57). The stalk regions of CD8 are interpreted to be highly flexible, but O-glycosylation may significantly restrict the flexibility of the stalks and the mobility of the CD8 head group relative to the T cell membrane (58)(59)(60). Therefore, "face-to-face" binding causes the cCD8aa binding orientation to pBF2*1501 and pBF2*0401 to skew towards the a2 domain and b2m, which might facilitate larger numbers of gd TCR to bind diverse peptides presented by limited BF2 alleles in chicken.…”

Section: Discussionmentioning

confidence: 99%

The Combination of CD8αα and Peptide-MHC-I in a Face-to-Face Mode Promotes Chicken γδT Cells Response

et al. 2020

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The CD8αα homodimer is crucial to both thymic T cell selection and the antigen recognition of cytotoxic T cells. The CD8-pMHC-I interaction can enhance CTL immunity via stabilizing the TCR-pMHC-I interaction and optimizing the cross-reactivity and Ag sensitivity of CD8+ T cells at various stages of development. To date, only human and mouse CD8-pMHC-I complexes have been determined. Here, we resolved the pBF2*1501 complex and the cCD8αα/pBF2*1501 and cCD8αα/pBF2*0401 complexes in nonmammals for the first time. Remarkably, cCD8αα/pBF2*1501 and the cCD8αα/pBF2*0401 complex both exhibited two binding modes, including an “antibody-like” mode similar to that of the known mammal CD8/pMHC-I complexes and a “face-to-face” mode that has been observed only in chickens to date. Compared to the “antibody-like” mode, the “face-to-face” binding mode changes the binding orientation of the cCD8αα homodimer to pMHC-I, which might facilitate abundant γδT cells to bind diverse peptides presented by limited BF2 alleles in chicken. Moreover, the forces involving in the interaction of cCD8αα/pBF2*1501 and the cCD8αα/pBF2*0401 are different in this two binding model, which might change the strength of the CD8-pMHC-I interaction, amplifying T cell cross-reactivity in chickens. The coreceptor CD8αα of TCR has evolved two peptide-MHC-I binding patterns in chickens, which might enhance the T cell response to major or emerging pathogens, including chicken-derived pathogens that are relevant to human health, such as high-pathogenicity influenza viruses.

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“…However, in the absence of structural information on the CD8 stalk, the model cannot establish anchor points for TCR and CD8 on the T cell membrane, as did the TCR–pMHC–CD4 structure (Figure 3A). While the TCR–pMHC–CD8 complex is probably not as conformationally constrained as the TCR–pMHC–CD4 complex, O -glycosylation of the CD8 stalk likely restricts its flexibility (36, 42), as discussed above. By limiting the mobility of the MHC-binding head group of CD8 in this way, O -glycosylation would impose constraints on the orientation of CD3 subunits relative to CD8-bound Lck, as does the rigid CD4 structure (Figure 4A).…”

Section: Implications For the Tcr–pmhc–cd8 Ternary Complexmentioning

confidence: 97%

“…Studies of mucins have demonstrated that O -glycans stiffen polypeptides through steric interactions between peptide-linked N -acetylgalactosamine residues and adjacent peptide residues (40, 41). Moreover, O -glycans in the CD8 stalk polypeptides were found to reduce the overall extension of the stalk from a theoretical maximum of 3.4 Å per residue to 2.6 Å per residue, indicating rigidification (36, 42). Therefore, O -glycosylation may limit the mobility of the CD8 head group relative to the T cell membrane, an important consideration in evaluating co-receptor interactions with TCR–pMHC during thymic selection and peripheral antigen recognition, as discussed below.…”

Section: Role Of the Cd8 Stalk Region In Co-receptor Functionmentioning

confidence: 98%

Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation

Li¹,

Yin²,

Mariuzza³

2013

Front. Immunol.

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T cell receptors (TCRs) recognize peptides presented by MHC molecules (pMHC) on an antigen-presenting cell (APC) to discriminate foreign from self-antigens and initiate adaptive immune responses. In addition, T cell activation generally requires binding of this same pMHC to a CD4 or CD8 co-receptor, resulting in assembly of a TCR–pMHC–CD4 or TCR–pMHC–CD8 complex and recruitment of Lck via its association with the co-receptor. Here we review structural and biophysical studies of CD4 and CD8 interactions with MHC molecules and TCR–pMHC complexes. Crystal structures have been determined of CD8αα and CD8αβ in complex with MHC class I, of CD4 bound to MHC class II, and of a complete TCR–pMHC–CD4 ternary complex. Additionally, the binding of these co-receptors to pMHC and TCR–pMHC ligands has been investigated both in solution and in situ at the T cell–APC interface. Together, these studies have provided key insights into the role of CD4 and CD8 in T cell activation, and into how these co-receptors focus TCR on MHC to guide TCR docking on pMHC during thymic T cell selection.

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Glycosylation and the Function of the T Cell Co-Receptor CD8

Cited by 7 publications

References 59 publications

Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4

Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4

The Combination of CD8αα and Peptide-MHC-I in a Face-to-Face Mode Promotes Chicken γδT Cells Response

Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation

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