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 peptide-major 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.

Fig. 1.

Pictorial representation of the computer simulations that were carried out. Three kinds of proteins (MHC, coreceptor, and TCR) were allowed to diffuse on the surface that represents 1 μm² of the T-cell–APC interface. Proteins were allowed to interact in accord with the indicated biochemical reactions. In the first set of simulations, reactions from scheme 1 were implemented; in the second set of simulations, reactions from scheme 2 were implemented. Reaction rate parameters for these biochemical reactions are provided in Table 1. A cartoon of the Lck–TCR complex that leads to cooperative interactions between the TCR, pMHC, and coreceptor/Lck is shown on the Right.

Fig. 2.

(A) Effective half-life of MHC on the T-cell surface as a function of k_off^{MHC-coreceptor} (which is proportional to affinity of the MHC–coreceptor interaction) as obtained in the first set of simulations (scheme 1 in Fig. 1). At k_off ∼ 20 s⁻¹ the half-life is enhanced by ∼1.5 times in the presence of coreceptor, whereas at k_off ∼ 80 s⁻¹ half-lives with and without coreceptor are statistically indistinguishable. (B) Levels of TCR phosphorylation as a function of k_off of the TCR–pMHC interaction. The results are obtained from simulations of 1 μm² of the T-cell–APC contact area with the following protein concentrations: 300 TCRs/μm², 100 coreceptors/μm² (black curve), or no coreceptor present (red curve). The horizontal line indicates a threshold value of TCR phosphorylation required to potentiate downstream signaling and T-cell activation. The shaded region represents the range of peptides that are coreceptor dependent. (C) Signal enhancement measured by TCR phosphorylation. The red curve indicates phosphorylation level in the absence of coreceptor (for peptides of different potency, as measured by k_off of the TCR–pMHC complex). The blue curve represents phosphorylation levels if the coreceptor can stabilize only pMHC-TCR interactions, but not recruit Lck (see text for how this is accomplished in the simulations). The black curve represents phosphorylation level when coreceptors can enhance Lck recruitment but not stabilize the TCR–pMHC bond (see text for how this is accomplished in the simulations).