Immunity & infection
CD4+ regulatory T (TREG) cells are critical mediators of peripheral immune tolerance and homeostasis and express the forkhead box p3 (Foxp3) transcription factor. TREG cells are abundant at mucosal surfaces, where they respond to local signals in order to adapt their transcriptional program. The consequences of these modifications on TREG cells remain largely unknown. To understand the processes involved, we compared the mRNA signature of Foxp3+ and exFoxp3+ T cells isolated from a model developed to study the reprogramming of TREG cells into Th1/Th17 effector T cells. We uncovered that the IL-33 receptor (IL-33R, ST2) was prominently expressed by T cells that maintained Foxp3 expression, while the IL-1 receptor (IL1R1) was expressed on cells that ultimately lost Foxp3. Interestingly, both ST2+ and IL1R1+ TREG cells populations compete for expansion under inflammatory conditions: the absence of IL1R1 expression (IL1R1-/-) leads to the accumulation of ST2+ TREG cells at mucosal surfaces, while IL-33 injections facilitate the accumulation of ST2+ TREG cells and reduce the onset of exFoxp3 T cells. Using lung infection models, we demonstrate that ST2-expressing TREG cells resist production of inflammatory cytokines, whereas IL1R1-expressing TREG cells express RORγT and proinflammatory cytokines. While IL-1 signalling impairs TREG cell suppressive function, IL-33 is required for the successful prevention of T-cell dependent colitis. Thus, ST2+ and IL1R1+ TREG represent two distinct populations of reprogrammed TREG cells. These observations demonstrate that IL-1 and IL-33 produced during immune challenge exert distinct roles on the functional adaptation of Foxp3+ TREG cells at mucosal surfaces during infections.