Effect of MHC clustering on antigen recognition and T cell responses

Abstract

Abstract MHC proteins that present peptide ligands to T cells form nano-scale clusters on the cell membrane of antigen-presenting cells. While MHC clustering is thought to influence antigen presentation to T cells and may depend on cell type and pathophysiological conditions, how the extent of MHC clustering controls productive TCR engagement and T cell responses has not been systematically studied. To evaluate the effect of MHC clustering on T cell responses, we utilized nano-scale discoidal membrane mimetics to capture and present pMHC ligands at various densities. We examined the binding parameters of these model membrane clusters interacting with live CD8+ T cells and their impact on the triggering of TCR signaling. Our data show that not just the level of expression of pMHC ligands but the extent of their clustering controls antigen recognition and responses by T cells. Variations in the density of pMHC with MHC clusters regulate CD8-MHC and TCR-pMHC interactions, each contributing in a unique way to antigen recognition and the quality of TCR-mediated signaling. Along with well-documented co-clustering of TCR and CD8 on activated, but not naïve T cells, these findings provide new understanding of how the immune receptor clustering controls the specificity and effectiveness of antigen-specific responses by naïve and activated T cells during acute and chronic viral infection.