Tolerogenic interactions between CD8 dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts.

The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8 dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8 DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8 DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8 DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8 DCs initiates tolerance induction. Tolerogenic CD8 DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8 DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol.