Introduction: MERTK is one of the TAM receptor tyrosine kinases (RTKs) that mediate homeostatic phagocytosis of apoptotic cells, and transmit regulatory signals that modulate immune response. Donor splenocytes (SP) treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (ECDI) is a potent negative vaccine for induction of donor-specific transplantation tolerance. Previous studies have shown that donor ECDI-SP require the apoptotic cell receptor MERTK to mediate their tolerogenic effects. However, the underlying mechanism of this requirement is unclear.

Methods: In this study, we address the mechanism of MERTK-mediated transplantation tolerance by donor ECDI-SP in BALB/c to C57BL6 heart as well as islet transplantation models.

Results: MERTK^-/- recipients exhibited markedly impaired transplant tolerance induction by donor ECDI-SP treatment in both allogeneic heart and islet transplant models. Mechanistically, MERTK^-/- macrophages produced a markedly elevated level of IFN-a upon co-culturing with allogeneic ECDI-SPs. The high level of IFN-a subsequently impaired the differentiation and function of myeloid derived suppressor cells (MDSCs). Specifically, IFN-a compromised MDSC suppression of antigen presenting cell-stimulated T cell proliferation. IFN-a receptor (IFN-aR) was found to be expressed on monocytic MDSCs, suggesting IFN-a may be able to directly affect MDSC function via IFN-aR signaling. Supporting this possibility, monocytic MDSCs treated with IFN-a were found to readily acquire robust antigen presenting capacity, while losing their immunosuppressive function. Furthermore, IFN-a led to a complete reversal of MDSCs-induced expansion of Tregs. In vivo, treatment of MERTK^-/- recipients with anti-IFNaR resulted in restoration of tolerance efficacy by donor ECDI-SP in both heart and islet transplantation models. Reciprocally, treatment of MERTK^+/+ recipients with IFN-a resulted in tolerance abrogation by donor ECDI-SP similar to that observed in MERTK^-/- recipients. These results underscore the critical role of recipient MERTK signaling in the suppression of IFN-a production upon donor ECDI-SP and the subsequent induction of a graft protective environment.

Conclusion: MERTK plays a critical role in mediating transplantation tolerance by donor ECDI-SP, likely via suppression of IFN-a production and maintaining the functional integrity of MDSCs and expansion of Tregs. Enhancement of MERTK signaling may represent a novel therapeutic target for tolerance induction for transplantation.

CITATION INFORMATION: Zhang L., DeBerge M., Thorp E., Luo X. MERTK Mediates Transplant Tolerance via IFN-a Regulation of MDSCs and Tregs Am J Transplant. 2017;17 (suppl 3).

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