Description:
<jats:title>Abstract</jats:title>
<jats:p>Initiation of an adaptive immune response occurs when peptides bound to class II MHC (MHCII) molecules expressed on the surface of Antigen Presenting Cells are recognized by CD4+ T Cells. Formation of peptide-MHCII complexes (pMHCII) occurs within acidic endosomal compartments. The effect of acid pH on peptide binding is well known, and is usually associated with an enhancement of binding and acceleration in kinetics relative to pH 7.4. We have shown that peptide binding to and release from MHCII at extracellular pH are function of structural permissiveness and affected by cooperative effects. To resolve whether cooperativity, thus system flexibility, is a function of pH, we measured the affinity of peptides derived from influenza H3 HA306-319 via cycle-mutation for the human MHCII allele HLA-DR1 (DR1) at pH 5.4, 6.4, and 7.4. In keeping with prior results, cooperativity affects peptide affinity in an exponential fashion, and increasing values of pH are associated to increasing values of cooperativity. This pH-dependence of cooperativity can be observed for destabilizing combinations of mutations, as well as for multiple substituted peptides whose binding is improved as compared to the single substituted sequences. These results indicate that the endosomal pH enhances system permissiveness with respect to extracellular conditions, increasing the probability of peptides with suboptimal chemistry to complex with MHCII.</jats:p>