The alarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3+ regulatory T cells during mucosal inflammation.

CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREG cells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREG cells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREG cells. In the absence of ST2, TREG cells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+ TREG over pro-inflammatory TREG cells in a Cryptococcus neoformans infection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREG cells, ultimately dictating the dynamics of adaptive immunity to pathogens.