IL-4Ralpha responsiveness by T cells prevents peripheral induction of FoxP3-expressing regulatory T cells during TH2-polarized immune response

Survival from Schistosoma mansoni infection requires the development of a finely regulated TH2-polarized immune response driven by the parasite egg antigens. A number of studies have proposed that S. mansoni egg antigens induce peripheral FoxP3-expressing regulatory T cells involved in the modulation of pro-inflammatory T helper immune responses (1-3). However, the tight regulation between antagonistic TH1, TH2 and Treg developmental programs in response to S. mansoni egg-antigens remains poorly understood.
In this study, we demonstrated in vitro that IL-4 strongly inhibits TGF1-induced FoxP3 expression by naive T cells and this inhibition is dependent on IL-4R expression on T cells. Surprisingly, wild-type mice that developed a strong TH2 immune response to S. mansoni egg antigens were able to modulate the magnitude of egg-induced inflammation in contrast to mice disrupted of IL-4R globally or specifically on T cells. The TH2 response developed by wild-type mice also prevented the induction of FoxP3-expressing CD4+ T cells in the draining lymph node. This was not apparent in LckcreIL-4R-/lox or IL-4R-/- mice. In addition, IL-4 neutralization in vivo promoted the induction of FoxP3+CD4+ cells in the draining lymph node. Finally, IL-4 responsiveness by T cells induced a CD103-expressing CD4+ T cell population which produced IL-10 in response to egg antigens.
Consequently, our study shows that the modulation of egg-induced inflammation is independent of FoxP3-expressing regulatory T cells but highlights a potential role of CD103-expressing CD4+ T cells as IL-10 producing regulatory T cells.