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Abstract
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-4Rα) 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-4Rα-deficient mice and demonstrated differential efficiency of IL-4Rα 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-4Rα 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-4Rα 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-4Rα-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-4Rα signaling in the positive regulation of Foxp3+ Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4Rα 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-4Rα-mediated signaling on Foxp3+ Treg cells to optimally control inflammation during helminth infections.
Highlights
Regulatory T (Treg) cells, the central component in the regulation of the immune system, play a pivotal role in the maintenance of self-tolerance and immune homeostasis [1]
Our newly generated mice did not show any sign of spontaneous inflammation during homeostasis, but when challenged with an experimental infection by parasitic worms, deletion of the IL-4 receptor from the regulatory T (Treg) cell population led to increased inflammation and aggravated tissue pathology
Recent reports have shown that augmentation of IL-4 receptor alpha (IL-4Rα) signaling through gain-offunction mutation [14,15] or chronic Type 2 inflammation [18] leads to a drastic reduction in forkhead box P3 (Foxp3)+ Treg cell population and impairment of Treg cell suppressive function, which in turn drive their reprogramming toward T helper 2 (Th2)-like or T helper 17 (Th17)-like cells [14,15,18], favoring the notion of an inhibitory role for this receptor in Treg cell function
Summary
Regulatory T (Treg) cells, the central component in the regulation of the immune system, play a pivotal role in the maintenance of self-tolerance and immune homeostasis [1]. Our knowledge of the intricacies of such regulation has considerably expanded Cytokines such as interleukin-2 (IL-2), interleukin-15 (IL-15) [2,3,4], interferon gamma (IFN-γ) [5,6], interleukin-12 (IL-12) [7], interleukin-6 (IL-6) [8,9], and interleukin-4 (IL-4) [10,11,12,13,14,15] have been reported to provide critical signals in the modulation of Treg cells’ development and function. Treatment of cluster of differentiation 4 (CD4)+ cluster of differentiation 25 (CD25)+ Treg cells in vitro with IL-4 has been shown to have an antiapoptotic role, an augmentation of the rate of Foxp expression, and potentiation of Foxp3+ Treg cell suppressive function [10], suggesting an unappreciated supporting role for IL-4Rα-mediated signaling in Foxp3+ Treg cell function in vitro yet to be validated in vivo
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