The Foxp3+ regulatory T-cell population requires IL-4Rα signaling to control inflammation during helminth infections

Forkhead box P3 (Foxp3(+)) regulatory T (Treg)-cell function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, interleukin-4 (IL-4)-mediated signaling via IL-4 receptor alpha (IL-4R alpha) mediates Treg cell transdifferentiation into ex-Foxp3 T helper 2 (Th2) or T helper 17 (Th17) cells. However, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. We generated Foxp3-specific IL-4R alpha-deficient mice and demonstrated differential efficiency of IL-4R alpha deletion in male (approximately 90%) and female (approximately 40%) animals, because of cyclic recombinase (Cre)-mediated X-linked foxp3 inactivation. Irrespective of the degree of IL-4R alpha deletion within the Foxp3(+) Treg cell population, mice showed exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections (Schistosoma mansoni or Nippostrongylus brasiliensis). Mechanistically, IL-4R alpha deletion in males and females led to a reduced expression of Foxp3 and subsequently an impaired accumulation of Foxp3(+) Treg cells to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4R alpha-mediated signaling during helminth infections decreased the ability of central Treg cells to convert into effector Treg (eTreg) cells and caused a significant down-regulation of markers associated with Treg cell migration (C-X-C motif chemokine receptor 3 [CXCR3]) and accumulation in inflamed tissues (GATA binding protein 3 [GATA3]) as well as survival (B cell lymphoma 2 [Bcl-2]). These findings unprecedentedly, to our knowledge, uncover a role for IL-4R alpha signaling in the positive regulation of Foxp3(+) Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4R alpha signaling in the negative regulation and transdifferentiation of Foxp3(+) Treg cells in vivo, our present findings reveal the host requirement for an intact, but not reduced or potentiated, IL-4R alpha-mediated signaling on Foxp3(+) Treg cells to optimally control inflammation during helminth infections.