Bone Morphogenic Protein signaling in Th/Treg lineage specification

摘要

Abstract The transforming growth factor-β (TGF-β) family cytokines regulate cell differentiation and morphogenesis, cell proliferation and migration, epithelial-to-mesenchymal transition and metastatic dissemination. TGF-β is an immunoregulatory cytokine well known to inhibit activation and differentiation of CD4+ effector cells and promote suppressor functions of Foxp3+ regulatory T cells. Despite increased understanding of how TGF-β regulates T cell functions, the immunomodulatory roles of many other members of the TGF-β cytokine family, especially bone morphogenetic proteins (BMPs), remain largely unknown. We have found that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3) expressed by naive and activated CD4+ T cells and Foxp3+ regulatory T (TR) cells, modulates functions effector Th and TR cells. Abrogating BMPR1α signaling leads to generation of pro-inflammatory Th1/Th17 effector cells expressing high levels of inflammatory cytokines, IFN-γ, IL-17 and TNF family proteins. BMPR1α-deficient CD4+ T cells do not generate adaptive TR (aTR) cells. Inactivation of BMPR1α gene in peripheral TR cells reduced Foxp3 expression leading to the instability of TR phenotype and accumulation of exTR cells. Jmjd3 (Kdm6b) demethylase was identified as target of BMPR1α signaling in TR cells and epigenetic changes as a cause of lost suppressor function. We hypothesize that BMPs and BMPR1α may represent regulatory modules shaping epigenetic landscape and priming T cells for transcriptional regulation mediated by TGF-β. BMPR1α is not the only receptor binding BMPs, these cytokines may also bind activin receptors including Alk2. To get further mechanistic insight how BMPs and TGF-β regulate functions of peripheral Th and TR cells we propose to generate conditional knockout mice where Alk2 gene is deleted in all T cells or in TR cells. Alk2 mutant mice will be compared to mice lacking BMPR1α gene in the respective T cell subsets. The goal of this proposal is to produce experimental mice which could be examined to understand how Alk2 and BMPR1α cooperate to deliver BMP and TGF-β mediated signaling to regulate CD4+ Th and TR cells.