Bone Morphogenic Proteins Are Immunoregulatory Cytokines Controlling FOXP3+ Treg Cells

Bone morphogenic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) cytokine family promoting differentiation, homeostasis, and self-renewal of multiple tissues. We show that signaling through the bone morphogenic protein receptor 1 alpha (BMPR1 alpha) sustains expression of FOXP3 in T-reg cells in peripheral lymphoid tissues. BMPR1 alpha signaling promotes molecular circuits supporting acquisition and preservation of T-reg cell phenotype and inhibiting differentiation of pro-inflammatory effector Th1/Th17 CD4(+) T cell. Mechanistically, increased expression of KDM6B (JMJD3) histone demethylase, an antagonist of the polycomb repressive complex 2, underlies lineage-specific changes of T cell phenotypes associated with abrogation of BMPR1 alpha signaling. These results reveal that BMPs are immunoregulatory cytokines mediating maturation and stability of peripheral FOXP3(+) regulatory T cells (T-reg cells) and controlling generation of iT(reg) cells. Thus, we establish that BMPs, a large cytokine family, are an essential link between stromal tissues and the adaptive immune system involved in sustaining tissue homeostasis by promoting immunological tolerance.