Exploring a possible role for the MHC Class II accessory molecule H2-O in the development of experimental autoimmune encephalomyelitis

HLA-DO (DO), or H2-O in mice, is a non-classical, non-polymorphic MHC Class II accessory molecule. Expressed primarily in the thymic medulla and B cells, little is known about its physiological role in vivo . To gain insight of what role DO might have in CD4 T cell selection, our laboratory has previously used in vitro biochemical experiments to show that DO binds peptide-receptive DR1 and enhances binding of DM-insensitive peptides to the HLA-DR1 molecule, while inhibiting the binding of DM-sensitive peptides. These observations led us to hypothesize that in vivo, DO might serve to optimize presentation of immunodominant epitopes in the thymic medulla; thereby ensuring proper negative selection in the thymus. Lack of DO then could lead to faulty negative selection and a larger precursor pool of autoreactive CD4 T cells in the periphery. To test this hypothesis, we utilized H2-O knock-out (KO) mice and the well characterized autoimmune murine model of experimental autoimmune encephalomyelitis (EAE). We found that H2-O KO mice have a faster onset of EAE when compared to C57BL/6 wild-type mice. The rapid onset of the disease correlates with the recovery of larger numbers of MOG tetramer specific CD4 T cells from the CNS of H2-O KO mice at all stages of disease. A comparison of MOG tetramer specific CD4 T cell precursors in naive H2-O KO and H2-O WT mice demonstrated larger numbers of MOG specific CD4 T cells in H2-O KO mice. Our data suggests that loss of DO correlates with an increase in the number of autoreactive MOG CD4 in KO mice likely due to faulty negative selection.