TSLP/dendritic cell axis promotes CD4(+) T cell tolerance to the gut microbiome

Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic function. To determine the function of TSLP in barrier sites, we investigated the impact of endogenous TSLP signaling on the homeostatic expansion of CD4(+) T cells in adult mice. Surprisingly, incoming CD4(+) T cells induced lethal colitis in adult Rag1-knockout animals that lacked the TSLP receptor (Rag1(KO)Tslpr(KO)). Endogenous TSLP signaling was required for reduced CD4(+) T cell proliferation, Treg differentiation, and homeostatic cytokine production. CD4(+) T cell expansion in Rag1(KO)Tslpr(KO) mice was dependent on the gut microbiome. The lethal colitis was rescued by parabiosis between Rag1(KO)Tslpr(KO) and Rag1(KO) animals and wild-type dendritic cells (DCs) suppressed CD4(+) T cell–induced colitis in Rag1(KO)Tslpr(KO) mice. A compromised T cell tolerance was noted in Tslpr(KO) adult colon, which was exacerbated by anti–PD-1 and anti–CTLA-4 therapy. These results reveal a critical peripheral tolerance axis between TSLP and DCs in the colon that blocks CD4(+) T cell activation against the commensal gut microbiome.