期刊
BLOOD
卷 129, 期 12, 页码 1718-1728出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-07-723015
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资金
- National Institutes of Health National Institute of Allergy and Infectious Diseases research [RO1-AI-037683]
- National Institutes of Health National Cancer Institute research [RO1-CA-16344105]
- National Institutes of Health National Heart, Lung, and Blood Institute research [PO1-HL-075462]
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.
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