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

Abstract

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 ...

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR–Ligand Off-Rates Measurements on Living Cells

“…The CD8 coreceptor enhances antigen recognition and T-cell activation by stabilizing TCR-pMHC interaction at the cell surface (28-31) and recruiting p56 lck to TCR/CD3 complex promoting cell signaling (32,33). Here, we demonstrate that CD8 strengthened the TCR-pMHC binding mainly by decreasing the TCR-pMHC dissociation by a factor of 3-to 4-fold (Fig.…”

Balancing specificity, sensitivity, and speed of ligand discrimination by zero-order ultraspecificity

“…Similarly to TCRs, the co-receptors CD4 and CD8 are also embedded in the plasma membrane [23]. The coreceptors is considered to bind to peptide-major histocompatibility complex (pMHC) [23,24], which is a complex of a ligand and MHC on the surface of an antigenpresenting cell, and Lck is considered to associate with the co-receptors [23][24][25]. Therefore, the assumption that ligand L itself has a catalytic function is reasonable if we admit that the complex of pMHC, CD4 or CD8, and Lck is necessary for TCR phosphorylation.…”

Phosphorylation of a Tyrosine Residue on Zap70 by Lck and Its Subsequent Binding via an SH2 Domain May Be a Key Gatekeeper of T Cell Receptor Signaling In Vivo

“…Computational and experimental work has shown the kinetics of CD8 to play an important role in T cell discrimination (23,32). Because CD8 is now effectively bound to the complex, not only through its interaction with the pMHC, but also through the Lck-Zap70 bond, we expect that an important feature of this model is that the off rate of CD8 from a TCR-pMHC will be effectively lowered.…”