Immunodeficiency and autoimmunity in H2-O deficient mice (P5016)

Abstract

Abstract HLA-DO/H2-O is a highly conserved non-polymorphic MHC class II-like molecule whose physiological function remains unknown. The cell maturation-dependent DO expression in B-lymphocytes and DCs suggests a role H2-O in promoting presentation of exogenous Ag by attenuating presentation of endogenous self-peptides. We report herein that H2-O-/- mice spontaneously develop high titers of IgG2a/c antinuclear antibodies (ANA) with specificity for dsDNA, ssDNA, and histones. Reconstitution of RAG1-/- mice with T and B cells from H2-O-/- or WT mice demonstrated that production of ANAs requires participation of CD4+ T cells from H2-O-/- mice. Bone marrow chimeras demonstrated that loss of H2-O expression in thymic epithelial cells did not induce ANAs, and that lack of H2-O expression in bone marrow-derived cells was sufficient to induce the autoimmune phenotype. Despite production of high titers of autoantibodies, H2-O-/- mice exhibit a delayed generation of humoral immunity to model antigens (OVA and KLH), affecting all major T-dependent Ig classes including IgG2a/c. Consistently, presentation of all the natural Ag epitopes by H2-O-/- APC was inefficient as compared to WT APC. Thus, H2-O promotes immunity towards exogenous Ag while preventing autoimmunity. We propose that H2-O, through spatially and temporally inhibiting H2-M, enhances presentation of exogenous antigen by preventing nascent/newly-synthesized class II molecules from forming stable complexes with endogenous self-peptides.