We report that the CD169+TIM-4+ tissue-resident macrophage (TRM) subset is the dominant tissue-resident leukocyte in skin, heart, and pancreas from C57BL/6 mice and skin and pancreas from humans. Following oxidative stress, CD169+TIM-4+ TRMs migrate to the draining lymph node and exhibit an immunoregulatory and hypostimulatory phenotype relative to migratory DCs, including higher expression of CD39, CD73, and galectin-9 and lower expression of CD80, CD86, and MHCII. In vitro, freshly isolated migratory CD169+TIM-4+ TRMs induce more Tregs (4.1+/-1.7%) as compared to migratory DCs (1.6+/-0.5%, p<0.01). Moreover, freshly isolated TRMs from pancreatic islets induced much greater FoxP3+ Treg conversion (20.9+/-6.12%) as compared to tissue-resident DCs (3.41+/-1.61%, p<0.001). Surprisingly, genetic deletion of TIM-4 protects CD169+TIM-4+ TRMs from apoptosis and increases their relative and absolute abundance in the draining lymph node. As a consequence, donor TIM-4 deletion prolongs cardiac allograft survival (MST=43 days with TIM-4KO donors vs. 17 days with wild type control donors, p<0.05) and generates cardiac allograft tolerance when combined with sub-therapeutic rapamycin therapy (MST was >120 days with TIM-4KO donors vs. 33 days with wild type control donors, p<0.001). We also report that a kindred CD169+ TRM subset is a dominant tissue-resident leukocyte in human skin and pancreas, suggesting that immunoregulatory TRMs are a therapeutic target in human solid organ transplantation.

CITATION INFORMATION: Thornley T, Kyriazis P, Agarwal K, Fang Z, Ma L, Chipashvili V, Koulmanda M, Strom T. Genetic TIM-4 Deletion Promotes Immunoregulatory Tissue-Resident Macrophage Survival and Lowers the Barrier to Cardiac Allograft Tolerance. Am J Transplant. 2016;16 (suppl 3).

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