The density of peptide-MHC ligands within nanoscale oligomers influences T-cell receptor mediated signaling

Y. Sykulev
Thomas Jefferson University, US

Keywords: MHC clusters, T-cell receptor, celllular signaling, cytotoxic T lymphocytes

Summary:

Because membrane ligands and receptors usually form nanoscale molecular assemblies or clusters, it is essential to develop model systems that can recapitulate this molecular clustering to study multivalent receptor-ligand interactions. To address this issue, we have tested various oligomers containing major histocompatibility complex (MHC) proteins bound to cognate (viral) and non-cognate (self) antigenic peptides recognizable by T-cell antigen receptor (TCR) on the surface of virus-specific human cytotoxic T lymphocytes (CTL). Several different nanoscaffolds have been utilized to assemble the peptide-MHC (pMHC) into oligomers. The binding and the ability to induce TCR-mediated signaling of various pMHC oligomers have been compared. We have found that the density of the pMHC within the oligomers and the multivalency of pMHC oligomers both could affect their binding and the stimulatory capacity. Importantly, the binding of non-cognate pMHC and their ability to facilitate recognition of cognate pMHC by CTL was depended on the density of non-cognate pMHC in the oligomers. These data will be discussed in view of mechanisms regulating recognition of self and viral pMHC by CTL on target and antigen-presenting cells.