Browning et al., Sci. Signal. 11, eaar2125 (2018) 28 August 2018 SCIENCE SIGNALING | RESEARCH ARTICLE 1 of 15 T CELLS TGF-b–mediated enhancement of T H 17 cell generation is inhibited by bone morphogenetic protein receptor 1a signaling Lauren M. Browning 1 , Maciej Pietrzak 2 , Michal Kuczma 3 , Colin P. Simms 1 , Agnieszka Kurczewska 1 , Justin M. Refugia 1 , Dustin J. Lowery 1 , Grzegorz Rempala 4 , Dmitriy Gutkin 5 , Leszek Ignatowicz 3 , Pawel Muranski 6 , Piotr Kraj 1 * The cytokines of the transforming growth factor–b (TGF-b) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-b, in regulating the immune responses has been extensively studied. TGF-b is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeosta- sis. In contrast, in the presence of proinflammatory cytokines, TGF-b promotes the differentiation of effector T helper 17 (T H 17) cells. Abrogating TGF-b receptor signaling prevents the development of interleukin-17 (IL-17)– secreting cells and protects mice from T H 17 cell–mediated autoimmunity. We found that the receptor of another member of TGF-b family, bone morphogenetic protein receptor 1a (BMPR1a), regulates T helper cell activation. We found that the differentiation of T H 17 cells from naive CD4 + T cells was inhibited in the presence of BMPs. Abrogation of BMPR1a 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-g, and TNF family cytokines and transcription factors defining the T H 17 cell lineage. We found that TGF-b and BMPs cooperated to establish effector cell functions and the cytokine profile of activated CD4 + T cells. Together, our data provide insight into the immuno- regulatory function of BMPs. INTRODUCTION The transforming growth factor–b (TGF-b) family of cytokines is important for promoting the homeostasis of various tissues and the differentiation of select immune cell subsets (1, 2). Family members, including TGF-bs and bone morphogenetic proteins (BMPs), are produced by both stromal and immune cells (3, 4). Different TGF-b family cytokines may have overlapping or opposing functions, al- though these effects are often dependent on cellular and cytokine context. A founding member of the family, TGF-b, is an essential regulator of T cell development and constrains self-reactivity of peripheral T cells and their responses to antigenic stimulation (5, 6). Mice deficient in TGF-b1 gene succumb to uncontrolled inflamma- tion and systemic, lethal autoimmune disease, which is mediated by exaggerated activation of T helper (T H ) effector cells, which produce interferon-g (IFN-g; T H 1) or interleukin-4 (IL-4; T H 2) (7, 8). These effects are due, in part, to the requirement of TGF-b for the develop- ment of Foxp3 + regulatory T (T reg ) cells, an immunoregulatory T cell subset (9, 10). Thus, TGF-b exerts cell-intrinsic and cell-extrinsic effects that prevent the activation of self-reactive peripheral T cells (11). Conversely, in an inflammatory environment, TGF-b supports the generation of pathogenic T H 17 cells, which secrete IL-17 (12). Loss of TGF-b signaling in T cells prevents IL-17 secretion and pro- tects mice from autoimmune encephalomyelitis after immunization with self-antigen (13). In promoting T H 17 cell generation, TGF-b cooperates with the proinflammatory cytokines IL-1, IL-6, or IL-21 and IL-23 (14–17). Activated T cells, including T H 17 and T reg cells, are the main source of TGF-b, which induces and sustains T H 17 cell differentiation (18). These findings underscore the importance of context-sensitive signaling and autocrine or paracrine TGF-b pro- duction for local immunoregulation. Despite our increased understanding of how TGF-b regulates T cell functions, the immunoregulatory roles of many other members of the TGF-b cytokine family, especially BMPs, remain largely un- known. BMPs represent the largest subgroup of TGF-b cytokine family (19). They control a wide range of biological activities in various cell types and play critical roles in morphogenesis of various tissues and organs. BMPs bind heteromeric complexes of type I [BMP receptor 1a (BMPR1a) and BMP receptor 1b (BMPR1b)] and type II (BMPR2) receptors to activate signal transduction pathways involving mothers against decapentaplegic homologs (or Smad1/5/8). BMPs can also regulate myeloid, B, natural killer, and peripheral T cells during in- fection, inflammation, and cancer (4, 20, 21). BMP2/4 or activin A increases the ability of TGF-b to promote generation of adaptive T reg (aT reg ) cells, which arise during immune responses to limit in- flammation (20, 22). Furthermore, BMPs increase phosphorylation of Runt-related transcription factor 1, which promotes IL-2 gene expression in conventional T cells and, in concert with Foxp3, in- hibits in T reg cells (23). BMPs are also involved in restraining in- flammation, but their exact role remains controversial (3). To test the role of BMPs in peripheral T cells, we generated mice lacking BMPR1a in T cells and found that BMPR1a-deficient T cells preferentially differentiated into T H 17 cells after activation. Tran- scriptome analysis suggested that loss of BMPR1a enhanced ex- pression of transcripts involved in T H 17 lineage commitment and inflammatory effector T cells. We showed that immunization with complete Freund’s adjuvant (CFA) stimulated stronger proinflam- matory responses in BMPR1a-deficient mice than in wild-type mice. Similarly, adoptive transfer of BMPR1a-deficient CD4 + cells into 1 Department of Biological Sciences, Old Dominion University, Norfolk, VA 23529, USA. 2 Department of Biomedical Informatics, Ohio State University, Columbus, OH 43210, USA. 3 Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. 4 College of Public Health, Ohio State University, Columbus, OH 43210, USA. 5 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15240, USA. 6 Columbia University Medical Center, New York, NY 10032, USA. *Corresponding author. Email: pkraj@odu.edu Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works on May 29, 2020 http://stke.sciencemag.org/ Downloaded from