The role of bone marrow promiscuous gene expression in peripheral tolerance

Abstract

Abstract For the negative selection of autoreactive T cells, peripheral tissue-restricted antigens (TRAs) are ectopically expressed and presented by medullary thymic epithelial cells (mTECs). This physiological property of mTECs, termed promiscuous gene expression (pGE), is predominantly regulated by the transcription factor, autoimmune regulator (AIRE). In the periphery, pGE was also found in secondary lymphoid organs and can induce peripheral immune tolerance. Bone marrow is an important organ known to prime naïve conventional T cells, as well as being a reservoir of regulatory T cells. However, the occurrence of pGE in the bone marrow is hitherto unknown. We hypothesize that a repertoire of auto-antigens is ectopically expressed and presented in the bone marrow, which maintains the peripheral tolerance of T cells. We investigated the presence of AIRE-expressing cells in bone marrow using a transgenic reporter mouse model in which GFP is expressed under the control of the AIRE promoter. AIRE expression was detected at both the RNA and protein levels. The bone marrow-resident AIRE-expressing cells (BMACs) anatomically locate adjacent to clusters of CD4+ T cells and express high levels of CD45, MHC-II and EpCAM. Their tolerogenic characteristic was conferred by the expression of PD-L1 and lack of costimulatory molecules CD80 and CD86. Gene expression analysis showed the AIRE-dependent TRA genes expressed in BMACs differ from those expressed in mTECs. BMACs were also detected at various frequencies in patients carrying different tumor entities. Our result demonstrates that the AIRE-expressing cells which ectopically express TRAs in the bone marrow could comprise the cellular basis for the induction of peripheral T-cell tolerance.