Loss of IFN-γ Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis by a Nonencephalitogenic Myelin Variant Antigen

Abstract

MHC variant peptides are analogues of immunogenic peptides involving alterations of the MHC-binding residues, thereby altering the affinity of the peptide for the MHC molecule. Recently, our laboratory demonstrated that immunization of WT B6 mice with 45D, a low-affinity MHC variant peptide of MOG35–55, results in significantly attenuated experimental autoimmune encephalomyelitis (EAE), yet IFN-γ production is comparable to myelin oligodendrocyte glycoprotein (MOG)35–55-immunized mice. In light of these findings, we asked whether IFN-γ was required for the reduced encephalitogenicity of the weak ligand 45D in EAE. In this study, we report that immunization of mice deficient in IFN-γ or its receptor with 45D exhibit significant EAE signs compared with 45D-immunized wild-type B6 mice. Moreover, 45D-immunized IFN-γ−/− and IFN-γR−/− mice demonstrate MOG tetramer-positive CD4+ T cells within the CNS and display substantial numbers of MOG-specific CD4+ T cells in the periphery. In contrast, wild-type mice immunized with 45D exhibit reduced numbers of MOG-specific CD4+ T cells in the periphery and lack MOG tetramer- positive CD4+ T cells in the CNS. Importantly, the increased encephalitogenicity of 45D in mice lacking IFN-γ or IFN-γR was not due to deviation toward an enhanced IL-17-secreting phenotype. These findings demonstrate that IFN-γ significantly attenuates the encephalitogenicity of 45D and are the first to highlight the importance of IFN-γ signaling in setting the threshold level of responsiveness of autoreactive CD4+ T cells to weak ligands.