Unique roles of TECs, DCs and B cells in Treg repertoire formation

Abstract

Abstract Foxp3+ CD4+ regulatory T cells (Treg) are an essential component in maintenance of immunological tolerance against self. Treg are generated in the thymus by relatively strong TCR recognition of self-peptide-MHCII complex (pMHCII) on antigen presenting cells (APCs). In addition to pMHCII dependent TCR signaling, B7 expression on APC is critical for Treg generation through CD28 co-stimulation. APCs that might be capable of providing such TCR/CD28 signaling to developing thymocytes include thymic epithelial cells (TECs), dendritic cells (DCs) and B cells. To date, however, how each APC contributes to the generation of the Treg repertoire specific for self-antigen under physiological condition is not fully understood. To address this question, we generated B7 conditional knockout mice enabling selective deletion of B7 from each APC type and assessed the effect of this cell type-specific perturbation of APC function on Treg generation. We first observed that B7 deletion from DCs, but not TECs or B cells, resulted in a substantial decrease in total Treg numbers. Interestingly combined B7 deletion from two (TECs + DCs) or three (TECs + DCs + B cells) APCs showed additive effects in decreasing the total Treg population size. In contrast, we found that the pMOG-specific Treg population depended on B7 on DCs, with no individual or additive effect of B7 deletion from TECs or B cells. These results suggested that TECs, DCs and B cells have unique and non-redundant roles in Treg repertoire formation. Further studies are currently underway to determine the role of TECs, DCs and B cells for the generation of Treg repertoires with distinct self-antigen specificities by utilizing panel of pMHCII-tetramers.