A tissue-resident macrophage specific coinhibitory molecule promotes regulatory T cell differentiation and stability

Abstract

Abstract CD4+Foxp3+ regulatory T (Treg) cells play a central role in the prevention of lethal autoimmunity and excessive inflammation. In contrast to their counterparts in lymphoid organs, Treg cells in non-lymphoid tissues acquire tissue-specific functional properties. While Treg tissue-tropisms are increasingly recognized, it remains poorly understood how tissue microenvironment influences Treg development, function and stability. Complement receptor of immunoglobulin family (CRIg) is a recently identified B7/CD28 family member. CRIg is exclusively expressed in tissue-resident macrophages. Earlier studies have found that CRIg functions as a coinhibitory molecule to suppress T cell proliferation and cytokine production. We here report a completely novel mechanism by which CRIg regulates T cell biology. We find that CRIg promotes the development of TGF-b induced regulatory T (iTreg) cells. More importantly, CRIg stabilizes the expression of Foxp3 in Treg cells by enhancing their responsiveness to IL-2. In vivo modulation of CRIg increases Treg abundancy and restores immune tolerance in autoimmune condition. In summary, these data shed new light on how tissue-resident macrophages impact tissue homeostasis by regulating the development and stability of Treg cells. CRIg may represent a tissue-specific immunomodulation to promote immune tolerance.