Abstract
We have previously generated a variant of the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide by mutation of the P6 MHC anchor residue from an S to a D amino acid. Here, we confirm previous findings that the 45D MHC variant peptide is incapable of inducing experimental autoimmune encephalomyelitis (EAE) despite its CD4 epitope bearing the same TCR contact residues as wildtype MOG epitope (wtMOG). Using the micropipette adhesion frequency assay (MP), we show that induction with 45D generates reduced levels of CD4 T cells specific for MOG in the CNS but not the periphery of asymptomatic mice. Importantly, 45D induction results in a loss of high affinity CD4 T cells, which could be responsible for initiation of disease. We also found changes in MOG-reactivity within the peripheral Treg compartment of 45D-induced mice. Together, the variant peptide alters the MOG-specific Teff and Treg response. Although the 45D mutation was designed to target the CD4 MOG epitope, it also changes the antigen responsible for expanding MOG-reactive CD8 T cells. We find that priming with 45D expands CD8 T cells with heightened affinity for MOG. Taken together, our data demonstrate that 45D may enhance peripheral tolerance mechanisms that ultimately aid in the protection from autoimmune disease.
