T-cell Progenitor-derived Dendritic Cells Contribute to the Repertoire Selection and Immunological Tolerance

BACKGROUND: Accumulating evidence indicates that bone marrow transplantation induces tolerance against simultaneously transplanted allogeneic organs; however, the mechanistic aspects of this phenomenon are less understood. It is known that early T-cell progenitors (ETPs) generate myeloid cells, such as dendritic cells (DCs) and macrophages, as well as T cells in the thymus. Here, we speculate that myeloid cells produced by ETPs may act as allogeneic antigen-presenting cells (APCs) and play an important role in T-cell selection, thereby contributing to tolerance induction. METHODS: To elucidate the contribution of ETP-derived APCs in T-cell selection, we sorted and cultured ETPs (CD4 - CD8 - c-Kit + CD25 - cells) in a combined ex vivo and in vivo system to generate T cells and APCs simultaneously, followed by a flow cytometric analysis of Vβ T-cell receptor (TCR). To evaluate the importance of ETP-derived APC in allogeneic tolerance, we transplanted ETP-reconstituted fetal thymus to athymic nude mice and performed skin transplantation. RESULTS: Flow cytometric analysis of the ETP culture showed the presence of CD11c + major histocompatibility complex class II + ETP-derived DCs, and the T cells generated in the culture showed a low frequency of specific TCR Vβ repertoire, suggesting clonal deletion. ETP-derived DCs also induced the deletion of a specific Vβ TCR repertoire in the in vitro coculture. Furthermore, nude recipients of ETP-reconstituted fetal thymus showed long-term allogeneic skin graft survival while third-party skin was rapidly rejected. CONCLUSIONS: The presence of ETP-derived APC is related to the deletion of specific Vβ TCR repertoire and skin allograft survival. By eliminating donor-reactive T-cell clones, ETPs may contribute to allograft tolerance.