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Abstract

Bone marrow (BM) serves as a site for T cell priming against blood-derived antigens but also harbors a diverse repertoire of regulatory T (Treg) cells. BM Treg cells are essential in hematopoiesis as they provide immune-privileged niches for hematopoietic stem cells, and are required for peripheral tolerance towards self-antigens. Treg cell accumulation in the BM has been hitherto viewed as a consequence of preferential immigration of thymus-derived Treg (tTreg) cells. However, it remains unknown whether Treg cells are also induced in situ in the BM, and to which degree these peripherally induced Treg (pTreg) cells contribute to the diversity of Treg cells in this lymphoid organ. Previously in our lab, a novel cell subset which expresses autoimmune regulator (Aire) has been identified in both murine and human BM. The BM Aire-expressing cells (BMACs) are characterized by the expression of major histocompatibility complex class II (MHC-II) and epithelial cell adhesion molecule (EpCAM). Moreover, they ectopically express a highly diverse repertoire of peripheral tissue-restricted self-antigens. The aim of this study is to characterize the cellular origin of BMACs, and evaluate their immunological function to induce peripheral tolerance, especially their role in the conversion of naïve T cells into Treg cells. In this study, I demonstrate that BMACs show features of CD19lowCD138+B220-Blimp-1+IgM+ plasma cells. They reside in proximity to CD4+ T cell clusters, express CD80, CD86, and PDL1 and are able to present Aire-regulated antigens to CD4+ T cells. Furthermore, BMACs overexpress genes associated with Treg induction, such as genes for retinoic acid production, the TIGIT ligand CD155 and IL-10. After encountering BMACs, which express the cognate antigen in BM, naïve CD4+ T cells specific for Aire-regulated antigens are converted to CD25+Foxp3+ Treg cells in vitro and in vivo. Treg cells induced by BMACs express high levels of CTLA-4 and LAP, and can suppress cytotoxic T cell responses in vivo. In conclusion, we have identified a plasma cell subset that expresses Aire and tissue-restricted self-antigens ectopically, and is capable to promote peripheral tolerance by inducing a repertoire of autoreactive Treg cells in the BM.