TY - JOUR TI - CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells AU - Yuan, Xiaomei AU - Yang, Bi-Huei AU - Dong, Yi AU - Yamamura, Asami AU - Fu, Wenxian A2 - Sakaguchi, Shimon VL - 6 PY - 2017 DA - 2017/11/24 SP - e29540 C1 - eLife 2017;6:e29540 DO - 10.7554/eLife.29540 UR - https://doi.org/10.7554/eLife.29540 AB - How tissue-resident macrophages (TRM) impact adaptive immune responses remains poorly understood. We report novel mechanisms by which TRMs regulate T cell activities at tissue sites. These mechanisms are mediated by the complement receptor of immunoglobulin family (CRIg). Using animal models for autoimmune type 1 diabetes (T1D), we found that CRIg+ TRMs formed a protective barrier surrounding pancreatic islets. Genetic ablation of CRIg exacerbated islet inflammation and local T cell activation. CRIg exhibited a dual function of attenuating early T cell activation and promoting the differentiation of Foxp3+ regulatory (Treg) cells. More importantly, CRIg stabilized the expression of Foxp3 in Treg cells, by enhancing their responsiveness to interleukin-2. The expression of CRIg in TRMs was postnatally regulated by gut microbial signals and metabolites. Thus, environmental cues instruct TRMs to express CRIg, which functions as an immune checkpoint molecule to regulate adaptive immunity and promote immune tolerance. KW - macrophages KW - T cells KW - immune checkpoint KW - immunological tolerance KW - inflammation KW - CRIg JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -