Investigating a role for the MHC class II accessory molecule HLA-DO in autoimmune disease

Abstract

Abstract HLA-DO (DO), 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 into what role DO might have in CD4 T cell selection, our lab previously used in vitro biochemical assays to show that DO itself enhances the binding of DM insensitive peptides to the HLA-DR1 molecule, while inhibiting the binding of DM sensitive peptides. This led us to hypothesize that in vivo, DO might be important for ensuring proper presentation of immunodominant epitopes in the thymic medulla; thereby ensuring proper negative selection occurs. Lack of DO then could lead to a larger precursor pool of autoreactive CD4+ T cells in the periphery due to faulty negative selection. To test this, we utilized H2-O knock-out (KO) mice and the autoimmune model experimental autoimmune encephalomyelitis (EAE). With this model, we have found that KO mice have a faster onset of disease when compared to C57BL/6 wild-type mice. This increase in onset correlated with the recovery of more MOG specific cells from the CNS of KO mice at all stages of disease. Moreover, naïve mouse data also supports our hypothesis with naïve KO mice having a larger number of MOG specific CD4+ T cells. More recently, we found that KO mice also harbor increased percentages of regulatory T cells (Tregs) in both the naïve and diseased states. Correlating this finding with disease onset, we saw that KO Tregs appear to have impaired upregulating of the inhibitory molecule CTLA-4 in early disease. As a whole, our data suggests that KO mice not only have an increased precursor pool of autoreactive CD4 T cells but might also have impaired Treg function; all leading to faster disease onset.