Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses

Significance

Here, we demonstrate that the cytokine activin-A instructs the differentiation of human IL-10–producing type 1 regulatory T (Tr1)-like cells that exhibit strongly suppressive functions against allergen-induced naive and effector CD4 ⁺ T-cell responses. In addition, we show that activin-A induces the activation of interferon regulatory factor (IRF4), which, along with aryl hydrocarbon receptor (AhR) and its binding partner, AhR nuclear translocator, forms a tripartite transcription factor complex that is essential for the differentiation and effector functions of human Tr1 cells. Importantly, administration of human activin-A–induced Tr1 cells in a humanized model of asthma confers protection against cardinal disease manifestations in preventive and therapeutic regimes. Collectively, our studies unravel a biological function for activin-A in the generation of suppressive human Tr1 cells that may be exploited for the control of allergic diseases.

Abstract

Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4 ⁺ T cells that express the Tr1-cell–associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4 ⁺ T cells. In fact, IRF4 silencing abrogates activin-A–driven IL10 and ICOS up-regulation and impairs the suppressive functions of human activin-A–induced Tr1-like (act-A–iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A–iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A–induced IRF4-aryl hydrocarbon receptor (AhR)–dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.