TGF-β–mediated enhancement of T _H 17 cell generation is inhibited by bone morphogenetic protein receptor 1α signaling

Abstract

The cytokines of the transforming growth factor-β (TGF-β) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-β, in regulating the immune responses has been extensively studied. TGF-β is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeostasis. In contrast, in the presence of proinflammatory cytokines, TGF-β promotes the differentiation of effector T helper 17 (T17) cells. Abrogating TGF-β receptor signaling prevents the development of interleukin-17 (IL-17)-secreting cells and protects mice from T17 cell-mediated autoimmunity. We found that the receptor of another member of TGF-β family, bone morphogenetic protein receptor 1α (BMPR1α), regulates T helper cell activation. We found that the differentiation of T17 cells from naive CD4 T cells was inhibited in the presence of BMPs. Abrogation of BMPR1α signaling during CD4 T cell activation induced a developmental program that led to the generation of inflammatory effector cells expressing large amounts of IL-17, IFN-γ, and TNF family cytokines and transcription factors defining the T17 cell lineage. We found that TGF-β and BMPs cooperated to establish effector cell functions and the cytokine profile of activated CD4 T cells. Together, our data provide insight into the immunoregulatory function of BMPs.

SMAD4 TGF-β–independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation

“…Interestingly, this indicates a potential interaction between SMAD4 and ETS or RUNX transcription factors that are important regulators of T cell differentiation and homeostasis ( 29 , 30 ), exemplifying that SMAD4 interacts with different partners to mediate its wide transcriptional impact in CD8 + T cells. Notably, BMP and activin, other members of the TGF-β family that signal through SMAD4, have been proposed to alter the biology of CD4 + T cells ( 31 , 32 ). However, treatment of either naive CD8 + T cells or activated CD8 + T cells with either BMP or activin failed to enforce the TGF-β–independent function of SMAD4 and alter the ability of TGF-β to induce CD103 expression ( Supplemental Figure 14 , A and B).…”

Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice

“…Tnfsf4 and Cd274 for instance can suppress IL-17A production in T cells 97,98 . Interestingly, adult cDC2 further showed higher expression of bone morphogenic protein 2 (Bmp2), which also suppresses IL-17A production from T cells 99 (Supplementary Fig. 6B).…”

BMPR2 expression level is correlated with low immune infiltration and predicts metastasis and poor survival in osteosarcoma

“…Studies have suggested that activated Bone Morphogenic Protein Receptor 1α (BMPR1α)-deficient CD4+ T cells produce a large amount of IFN-γ and enhance tumor proliferation, indicating the adverse effect of BMP signaling on the adaptive immune response (53). Abrogation of BMPR1α signaling during CD4+ T cell activation induced inflammatory effector cells to express various of cytokines such as IL-17, IFN-γ, and TNF family and transcription factors defining the Th17 cell lineage (54). BMPs and BMPRs also serve an important role during the process of B cell activation (55).…”