Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 (Th2) cells. However, simultaneous expansion of regulatory CD4⁺Foxp3⁺ T (Treg) cells impedes protective responses, resulting in chronic infections. The ratio between regulatory and effector T cells can therefore determine the outcome of infection. The re-differentiation of Treg into T helper (Th) cells has been identified in hyper inflammatory diseases, requiring a revision of this model. In this study, we asked whether ex-Foxp3 Th2 cells develop and contribute to type 2 immunity following helminth infection or airway allergy. Using a variety of multi-gene reporter and fate reporter systems we demonstrate that a significant proportion of Th2 cells derive from Foxp3⁺ cells and participate in the type 2 immune response following Heligmosomoides polygyrus infection or airway allergy. Ex-Foxp3 Th2 cells exhibited characteristic Th2 effector functions, activating macrophages and providing immunity to H. polygyrus. Phosphorylated STAT6 in response to IL-4 converted Treg cells to Th2 cells in vitro and in vivo with selective deletion of Il4ra on Foxp3⁺ cells reducing ex-Foxp3 Th2 cells following H. polygyrus infection, but not during airway allergy. Collectively, our findings indicate that converting Treg cells into Th2 cells can concomitantly enhance Th2 cells and limit Treg-mediated suppression.