TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation

Thymic stromal lymphopoietin (TSLP) is a type I cytokine that promotes allergic responses and mediates type 2 immunity. A balance between effector T cells (Teff), which drive the immune response, and regulatory T cells (Tregs), which suppress the response, is required for proper immune homeostasis. Here, we report that TSLP differentially acts on Teff versus Tregs to balance type 2 immunity. As expected, deletion of TSLPR on all T cells (Cd4CreCrlf2fl/fl mice) resulted in lower numbers of Th2 cells and diminished ovalbumin-induced airway inflammation, but selective deletion of TSLPR on Tregs (Foxp3YFP-Cre/YCrlf2fl/fl mice) resulted in increased IL-5- and IL-13-secreting Th2 cells and lung eosinophilia. Moreover, TSLP augmented the expression of factors that stabilize Tregs. During type 2 immune responses, TSLPR-deficient Tregs acquired Th2-like properties, with augmented GATA3 expression and secretion of IL-13. TSLP is not only a driver of Th2 effector cells but also acts in a negative feedback loop, thus promoting the ability of Tregs to limit allergic inflammation. RNA-sequencing was performed using total RNA from nTregs with TCR in the absence versus presence of TSLP and also Tregs from Foxp3YFP-Cre/YCrlf2fl/fl and Foxp3YFP-Cre isolated from allergic lung tissue.