Activin-A is a critical inducer of human CD4+ICOS+IL-10-secreting regulatory T cells that suppress allergen-driven T cell responses in vitroand experimental asthma in a humanized mouse model in vivo

Introduction: Regulatory T cells (Tregs) are essential for the maintenance of airway tolerance.We have shown that activin-A induces mouse Tregs that protect from asthma in vivo . Still, whether activin-A can induce human Tregs remains elusive. Methods: The suppressive functions of activin-A-treated T cells on allergic responses in vitro were studied.We examined the effects of activin-A-treated T cells in asthma protection in a humanized mouse model of asthma. Results: We show that activin-A restrains human T cell responses during allergenic stimulation in vitro .Activin-A induces CD4 + ICOS + IL-10-secreting Tregs (act-A-iTregs) that inhibit allergen-driven proliferation and cytokine release by T responders.Using a humanized mouse model, we show that adoptive transfer of act-A-iTregs in vivo ameliorates key asthma features, such as airway hyperresponsiveness and lung inflammation.Of clinical relevance, act-A-iTregs suppress Th2 responses of asthmatics ex vivo .Act-A-iTregs exhibit a major increase of the expression of the transcription factors, aryl hydrocarbon receptor (AhR), c-Maf and interferon regulatory factor 4 (IRF4).ChIP experiments reveal that AhR, c-Maf and IRF4 bind to their putative binding sites in ICOS and IL10 loci and cooperate to induce their expression in act-A-iTregs.Addition of an AhR antagonist reverses activin-A-mediated induction of ICOS + IL-10 + Tregs, indicating a novel link between activin-A and AhR in human Treg generation. Conclusion: Our data may facilitate the use of act-A-iTregs in adoptive-transfer therapeutic regimes aiming to re-establish tolerance in asthma.