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

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.cytokines | allergic inflammation | immune regulation | activin-A | human T regulatory cells

Engineered T Regulatory Type 1 Cells for Clinical Application

“…In the latter study, it was proposed that while BAFT is required for both Th17 and Tr1 cell induction, IRF4 and IRF1 are differentially required for the two cell subsets ( 31 ). However, this conclusion is in contrast with the demonstration that activin-A promotes human Tr1 cells via activation of IRF4 that along with AhR binds to IL-10 and icos promoters ( 32 ). Moreover, ITK signaling via Ras/IRF4 pathway regulates the induction and function of both murine IL-27-induced Tr1 cells and human IL-10-induced Tr1 cells ( 33 ).…”

Impact of weather and climate change with indoor and outdoor air quality in asthma: A Work Group Report of the AAAAI Environmental Exposure and Respiratory Health Committee

“…58,67,72,73 Ambient air pollution and polycyclic aromatic hydrocarbon exposure has also been shown to impair regulatory T-cell function in asthmatic patients, 74,75 but it is also recognized that signaling through the aryl hydrocarbon receptor induces human regulatory T cells. 76 Generation of free radicals by these particulate components, in addition to a contribution from semivolatile organic components and gases, such as ozone, nitrogen oxides, and sulfur dioxide, can induce oxidative stress, which can lead to further proinflammatory effects in the respiratory tract and lung. 63,67,73 Although the effect of individual air pollutants might be unique, the combined effect of exposure spikes or chronic low-level exposure to a mixture of airborne pollutants can result in a pronounced effect on patients with underlying allergic or nonallergic asthmatic disease.…”

Characterisation of anti-parasitic CD4+ T cell responses during malaria

“…Tr1 cells do not have a defining transcription factor, although a number of transcription factors have been attributed with control of IL-10 production in these cells 236,238,317 . Given that PBX1, a transcription factor and pioneer factor 351,352 , was transcriptionally up-regulated in Tr1 cells in both humans and mice, it was possible that it functioned as a master transcription factor governing the phenotype and function of these cells.…”

“…Their potent immunosuppressive characteristic is primarily attributed to IL-10, which is known to widely suppress inflammatory responses. However, they also express other regulatory molecules, including TGFβ, ICOS, and LAG-3 254,308,317 . In addition to their classical suppressive functions, TGFβ and ICOS can act in a positive feedback loop to enhance and maintain IL-10 production by Tr1 cells, though they are not essential for IL-10 initiation 237,238 .…”

“…cMAF and AHR are also important for IL-10 production in Tr1 cells 238 . These transcription factors act in synergy with each other and other transcription factors like IRF4 to activate IL-10 transcription 289,317 . cMAF and AHR also trans-activated the IL-21 gene promoter which acts in a positive feedback loop to induce cMAF, AHR, which in turn potentiates IL-10 production 238 .…”