TSLP acts on Tregs to limit effector Th2 cell generation during type 2 immune responses

Abstract Thymic stromal lymphopoietin (TSLP) is a type 2 alarmin secreted by epithelial cells to promote type 2 inflammation. After antigen recognition, naïve CD4 T cells differentiate into effector T (Teff) cells, whereas regulatory T (Tregs) cells suppress the immune response to prevent adverse effects caused by inflammation. Therefore, a delicate balance between Teff and Treg activity is required for the homeostasis of immune responses. Here we generated a TSLPR conditional KO mice (Crlf2fl/fl) to investigate the functional role(s) of TSLP on Teff and Tregs. Conditional deletion of TSLPR on T cells (Cd4CreCrlf2fl/fl) resulted in lower numbers of eosinophils and Th2 cells with OVA-induced airway inflammation. In contrast, conditional deletion of TSLPR on Tregs (Foxp3CreCrlf2fl/fl) resulted in elevated numbers of eosinophils and increased IL-5- and IL-13-secreting effector Th2 cells. Furthermore, phenotypic analysis of Foxp3 +Tregs during type 2 immune responses shows that Tregs from Foxp3CreCrlf2fl/flmice have upregulated levels of GATA3 and secrete IL-13. Together, these data indicate that TSLP not only promotes suppressive activity by Tregs in the generation of Th2 cell-mediated responses but that it also restrains GATA3 production and IL-13 secretion by the Treg cells, indicating a key role for TSLP in shaping an immunosuppressive environment during type 2 immune responses. This research was supported by the Intramural Research Programs of NHLBI, NIH.