Bone Morphogenic Protein Receptor 1α and its ligands as a signaling circuit modulating immune response

Abstract

Abstract Despite increased understanding of how the transforming growth factor-β (TGF-β) regulates T cell functions, the immunomodulatory roles of other members of the TGF-β cytokine family, especially bone morphogenetic proteins, remain largely unknown. We have found that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3) expressed by activated effector and regulatory CD4+ T cells, modulates functions of both of these cell types by promoting generation of adaptive TR and inhibiting generation of Th17 cells from naive CD4+ T cells. Mice where BMPR1α is deleted in T cells (BMPR1αT− mice) had a decreased proportion of thymic derived TR cells. Activation of BMPR1α deficient (BMPR1α−) CD4+ T cells leads to generation of Th1/Th17-like effector cells expressing high levels of inflammatory cytokines, including IFN-γ, IL-17 and TNF family proteins. Effector CD4+ T cells activated by dendritic cells expressing BMP inhibitors expressed lower levels of PD1. Immunization of BMPR1αT− mice induced vigorous inflammatory response and mice were able to better control B16 melanoma tumors. Tumor infiltrate had very few TR cells and higher proportion of CD8+ T cells compared to tumors in wild type mice. These data demonstrate that TGF-β mediated immunosuppression in the course of tumor growth can be bypassed by inhibition of BMPR1α signaling. Transcriptome analysis of wild type and BMPR1α− CD4+ Th cells revealed differential expression of transcription factors, cytokines and cytokine receptors and signaling molecules essential to establish regulatory networks supporting Th17 or TR cells. This suggests that BMPR1α is a potential target to augment effector Th cell responses.