Immunoregulatory tissue resident macrophage subsets have been reported in skin, heart, lung and adipose tissue.We now demonstrate the existence of a functionally immunoregulatory population of CD169+ TIM-4+ tissue resident macrophages that dwell in human and mice islets. These specialized macrophages induce antigen-specific Tregs. To compare the phenotype of islet resident macrophages (IRMs) and islet resident dendritic cells (IRDCs), we selected FACS-sorted IRMs and IRDCs from mouse islets by qPCR analysis. Akin to other populations of tissue-resident macrophages, we also detected higher levels of immunoregulatory CD39, CD73 and galectin-9 in IRMs relative to IRDCs. Co-culturing IRMs and IRDCs with naive CD4+ T cells in the mixed lymphocyte reaction we determined that IRM stimulators induced 20.9 +/- 6.12% of activated CD4 T cells to express FoxP3 as compared to 3.41 +/- 1.61% of IRDC stimulated T cells or 2.07 +/- 0.66% of splenic DC stimulated T cells in 5 independent experiments. In the T1D NOD mice model we have shown that as T1D approaches, the immunoregulatory phenotype of IRMs is diminished, as is their relative abundance as compared to immunoinflammatory DCs. The ratio of IRDCs relative to IRMs is dramatically increased in 9 week-old NOD mice (p<0.01) and 15-week-old NOD(p<0.001) mice but no significant difference is observed in non autoimmune mice. TIM-4 blockade improves the survival of tissue-resident macrophages thereby prolonging heart allograft survival. Importantly, we found that blockade of TIM-4 prolonged the survival of fully allogeneic islet allografts (MST=43 days, n=5) when compared to wild type islets transplanted into wild type mice (MST=17 days, n=4, p<0.05). Furthermore, 2/5 transplants in the TIM-4 blockade group lasted >110 days whereas all mice in the control group rejected by day 10. In conclusion, we have identified a novel subset of immunoregulatory IRMs that powerfully induces Tregs and attenuates local inflammation. We believe that maintenance of IRM abundance and their immunoregulatory phenotype increases islet allograft survival and constitutes a potential therapeutic strategy to prevent and/or cure T1D.

CITATION INFORMATION: Kyriazis P, Thornley T, Agarwal K, Ma L, Strom T, Koulmanda M. Maintenance of the Phenotype and Abundance of Islet-Resident Macrophages Promotes Islet Graft Survival and Appears to Prevent Type 1 Diabetes. Am J Transplant. 2017;17 (suppl 3).

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