MHC clustering regulates selectivity and effectiveness of T-cell responses

Abstract

Abstract Although formation of nano-scale MHC clusters on the cell membrane of antigen-presenting cells has been well documented, the essence of MHC clustering and the role in controlling antigen presentation and T-cell responses have been not systematically studied. This is due to the absence of available approaches to evaluate how the clusters’ size, density and composition of MHC clusters influence TCR engagement and triggering of TCR signaling. We exploited nano-scale discoidal membrane mimetics (nanolipoprotein particles, or NLPs) to capture and present pMHC ligands at various densities and examined the binding of these model membrane clusters to the surface of live human CD8+ T cells and the subsequent triggering of intracellular Ca2+ signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8-MHC interactions, and relatively long lifetime of cognate TCR-pMHC complexes emerge as essential parameters explaining the significance of MHC clustering. Rapid rebinding of CD8 to clustered MHC suggests a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T-cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate antigen recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T-cell responses.