Role of MHC class II in Treg-mediated tolerance to allogeneic transplants (126.26)

Abstract

Abstract Transfer of donor MHC class II genes (MHCII) in the bone marrow of recipients of allografts induced tolerance spreading to all alloantigens. Tolerance was donor MHCII-specific, transferable only via host CD4 Tregs and selectively induced by MHCII gene therapy. Studies on the fate of transgenic MHCII molecules revealed that both the α and β chains provided peptides presented on the MHCII of bone marrow-derived antigen-presenting cells (APCs). Transgene-matched graft MHCII was critical for survival as donor MHCII-treated recipients promptly rejected MHCII-deficient transplants. Next, the role of thymic transgenic MHCII peptides on Treg development was studied in a model recapitulating MHCII peptide presentation: the IEα 52-68 peptide/IAb complexes recognized by the YA-e mAb and TEa transgenic TCR. With this model we showed that 1) the highly conserved IEα sequence was dominantly exposed on all dendritic cells located in the thymic medulla, the birthplace of Tregs, and 2) transfer of the IEα peptide into IEneg mice via bone marrow transplantation, converted host IEα-specific CD4 T cells into CD4+ CD25+ Foxp3+ Tregs. These data are consistent with a dominant role of MHCII peptides in shaping Treg TCR specificity and differentiation. They also propose a mechanism for MHCII-tolerance: MHCII-specific Tregs require activation by cognate MHCII peptide provided by MHCII-matched transplants prior to suppressing alloreactive T cells of different TCR specificity.