Ubiquitination of MHC Class II Is Required for Development of Regulatory but Not Conventional CD4+ T Cells

Abstract

MHC class II (MHC II) displays peptides at the cell surface, a process critical for CD4(+) T cell development and priming. Ubiquitination is a mechanism that dictates surface MHC II with the attachment of a polyubiquitin chain to peptide-loaded MHC II, promoting its traffic away from the plasma membrane. In this study, we have examined how MHC II ubiquitination impacts the composition and function of both conventional CD4(+) T cell and regulatory T cell (T-reg) compartments. Responses were examined in two models of altered MHC II ubiquitination: MHCIIKRKI/KI mice that express a mutant MHC II unable to be ubiquitinated or mice that lack membrane-associated RING-CH 8 (MARCH8), the E3 ubiquitin ligase responsible for MHC II ubiquitination specifically in thymic epithelial cells. Conventional CD4(+) T cell populations in thymus, blood, and spleen of MHCIIKR KIIKI and March8(-/-) mice were largely unaltered. In MLRs, March8(-/-), but not MHCIIKR KIIKI, CD4+ T cells had reduced reactivity to both self- and allogeneic MHC IL Thymic T-reg were significantly reduced in MHCIIKR KIIKI mice, but not March8(-/-) mice, whereas splenic T-reg were unaffected. Neither scenario provoked autoimmunity, with no evidence of immunohistopathology and normal levels of autoantibody. In summary, MHC II ubiquitination in specific APC types does not have a major impact on the conventional CD4(+) T cell compartment but is important for T-reg development.