The role of peptide-MHC ligand density in stimulating T-cell receptor signaling (58.21)

Abstract

Abstract Cell surface MHC proteins form clusters on the cell membrane. The MHC density within clusters could affect recognition of noncognate (self) and cognate peptide-MHC (pMHC) ligands and influence the kinetics of TCR-mediate signaling and quality of T cell responses. To evaluate the role of density, orientation and valency of pMHC ligands we utilized different scaffolds to assemble pMHC oligomers modeling MHC clusters. We systematically investigated how these parameters influence the binding of the pMHC oligomers to live CD8+ cytotoxic T lymphocytes (CTL) and the kinetics of TCR-mediated signaling. We have found that the recognition of noncognate or self pMHC strongly depends on the pMHC density and architecture and size of the scaffolds. In contrast, the valency but not the pMHC density mostly determined the recognition of strong agonist pMHC ligands. In addition, the pMHC density significantly influences the ability of cognate and noncognate pMHC to cooperate and to induce robust and rapid TCR signaling. The latter regulates the kinetics of target cell destruction by CTL that is essential for successful anti-virus immunity.