The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

Hutchinson, Sarah; Wooldridge, Linda; Tafuro, Sabrina; Laugel, Bruno; Glick, Meir; Boulter, Jonathan M.; Jakobsen, Bent K.; Price, David A.; Sewell, Andrew K.

doi:10.1074/jbc.m300633200

Cited by 86 publications

(117 citation statements)

References 71 publications

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“…This result, in fact, has been observed in experiments by Sewell and coworkers (28), where a panel of MHC class I with mutated CD8 binding sites (11,28,29) was studied. They found that MHC mutants with a 10-fold weaker than WT affinity for CD8 were still able to activate T cells to the same extent (28). This result is consistent with our finding that the strength of CD8-MHC interactions that stabilize TCR-pMHC interactions contributes little to enhancing signaling.…”

Section: Discussionsupporting

confidence: 66%

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Artyomov

Lis

Devadas

et al. 2010

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

173

144

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The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptidemajor histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR-pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr-pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function.M embrane proteins CD4 and CD8 are expressed on T helper cells and cytotoxic T lymphocytes, respectively, that are known to augment the sensitivity and response of T cells to cognate peptide-major histocompatibility (pMHC) ligands (1-3). It is generally thought that the ability of these coreceptors to enhance T-cell responses is due to two main effects: (i) Binding of CD4 and CD8 to MHC class II and class I molecules helps stabilize weak T-cell receptor (TCR)-pMHC interactions; and (ii) the Src kinase, Lck, which is bound to the cytoplasmic tail of coreceptors, is efficiently recruited to the TCR complex upon coreceptor binding to the MHC, thereby enhancing the initiation of TCR signaling (3, 4).Surface plasmon resonance (SPR) analyses show that the halflives characterizing coreceptor-MHC interactions are <35 ms (off rate >20 s −1 , the resolution of SPR instruments) for both CD4 and CD8 (5-7). It is difficult to understand how the two effects noted above can be potentiated by such fleeting interactions. For example, consider the effect of coreceptor-MHC interactions in stabilizing the TCR-pMHC complex. A typical agonist pMHC ligand is bound to a TCR for ≈10,000 ms (corresponding to an off rate of 0.1 s −1 ) (8). Thus, during the lifetime of the TCR-pMHC bond a coreceptor would disengage from the MHC ≈1,000 times, making it implausible that stabilization of TCR-pMHC interactions would be achieved. Recent data measuring TCR binding within a synapse (9) show that it is less stable, perhaps 1,000 ms for an average TCR-ligand interaction due to actin polymerization activity, but this is still far in excess of what has been reported for CD4 and CD8 interactions.However, CD8 has been found to stabilize pMHC binding to CD8+ T-cell surfaces (10, 11) and augment sensitivity (2, 12). In contrast, past studies (13,14) and recent in situ measurements at intercellular junctions show that CD4 does not stabilize the interactions of TCR with class II pMHC molecules (9). However, CD4 does enhance the sensitivity of T helper cells (1,9,15,16). As the binding affinity of CD4 for the MHC ectodomain has been reported to be ...

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Section: Discussionsupporting

confidence: 66%

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Artyomov

Lis

Devadas

et al. 2010

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

173

144

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“…The above-proposed mechanism of CD8-TCR cooperation also explains how the weaker CD8-pMHC interaction compared with the TCR-pMHC one, has such a strong contribution in T-cell activation [49]. As suggested above, the pMHC complex formation with proximal CD8 and TCR is assumed to proceed at the rate determined by the CD8-pMHC association.…”

Section: Mechanism Of Pmhc Association With T-cellsmentioning

confidence: 80%

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Pecht

Gakamsky

2005

FEBS Letters

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The interactions between the TCR and peptides bound to class I MHC encoded molecules (pMHC) and a mechanism for CD8 cooperation in this process are reviewed. Observation of two TCR/CD8 populations with different lateral diffusion rate constants as well as two distinct association phases of class I MHC tetramers ((pMHC) 4 ) with T-cells suggest that the most efficient pMHC-T-cell association route corresponds to a fast tetramer binding to a colocalized CD8/TCR population, which apparently resides within membrane rafts. Thus, ligandcell association starts by pMHC binding to the CD8. This rather fast step promotes pMHC association with CD8-proximal TCRs and thereby enhances the overall association process. The model suggests that this raft-associated CD8-TCR subpopulation is responsible for evoking T-cell activation.

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“…It seems extremely unlikely that the striking biophysical characteristics of the pMHCI/CD8 interaction have occurred by accident. Indeed, this conclusion is strengthened by the finding that the pMHCI/CD8 interaction is capable of exerting the vast majority of its biological function when weakened even further (21), which suggests that CD8 has specifically evolved to operate at very low solution affinities.…”

mentioning

confidence: 99%

MHC Class I Molecules with Superenhanced CD8 Binding Properties Bypass the Requirement for Cognate TCR Recognition and Nonspecifically Activate CTLs

Wooldridge

Clement

Lissina

et al. 2010

The Journal of Immunology

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CD8+ cytotoxic T lymphocytes (CTL) are essential for effective immune defence against intracellular microbes and neoplasia. CTL recognize short peptide fragments presented in association with major histocompatibility complex class I (MHCI) molecules on the surface of infected or dysregulated cells. Antigen recognition involves the binding of both T cell receptor (TCR) and CD8 co-receptor to a single ligand (pMHCI). The TCR/pMHCI interaction confers antigen specificity, whereas the pMHCI/CD8 interaction mediates enhanced sensitivity to antigen. Striking biophysical differences exist between the TCR/pMHCI and pMHCI/CD8 interactions; indeed, the pMHCI/CD8 interaction can be >100-fold weaker than the cognate TCR/pMHCI interaction. Here, we show that increasing the strength of the pMHCI/CD8 interaction by ~15-fold results in non-specific, cognate antigen-independent pMHCI tetramer binding at the cell surface. Furthermore, pMHCI molecules with super-enhanced affinity for CD8 activate CTL in the absence of a specific TCR/pMHCI interaction to elicit a full range of effector functions, including cytokine/chemokine release, degranulation and proliferation. Thus, the low solution binding affinity of the pMHCI/CD8 interaction is essential for the maintenance of CTL antigen specificity.

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The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

Cited by 86 publications

References 71 publications

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

MHC Class I Molecules with Superenhanced CD8 Binding Properties Bypass the Requirement for Cognate TCR Recognition and Nonspecifically Activate CTLs

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The CD8 T Cell Coreceptor Exhibits Disproportionate Biological Activity at Extremely Low Binding Affinities

Cited by 86 publications

References 71 publications

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T‐cells

MHC Class I Molecules with Superenhanced CD8 Binding Properties Bypass the Requirement for Cognate TCR Recognition and Nonspecifically Activate CTLs

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Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells