TSLP interacts with a heterodimeric receptor consisting of the TSLP receptor (TSLPR) chain and the IL-7Rα chain to activate several pathways, including JAK1/2, STAT5, PI3K, and NF-κB ( 11). However, IL-33 shows differential expression and IL-25 is undetectable in a subset of the barrier organs ( 9, 10). Thus, it is critical to determine the expression and function of type 2 alarmins during the homeostatic T cell proliferation at barrier organs.Īmong type 2 alarmin cytokines, TSLP is found to be uniformly expressed under steady-state conditions across the barrier organs ( 7, 8). Homeostatic T cell expansion is implicated in the maintenance of peripheral T cells and regulation of barrier immunity however, the precise mechanism underlying homeostatic T cell expansion and the role of type 2 alarmin cytokines in this process are unclear ( 5, 6). However, IL-25, IL-33, and TSLP have been mostly studied for their role in the induction of allergic inflammation at barrier sites ( 4) and it is unclear whether these cytokines play any role in other inflammatory conditions that affect barrier organs. These cytokines are known to protect the host against helminth and parasitic infections ( 3). Among them, the type 2 alarmins, interleukin 25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) skew barrier immune responses toward type 2 immunity, which includes Th2 differentiation, IgE class switching of B cells, and the induction mast cells and eosinophils ( 2). Alarmin cytokines released at barrier sites are known to mediate an initiating alarm signal to tissue-resident and circulating immune cells ( 1). The barrier organs, including the skin, lung, and gastrointestinal (GI) tract, are essential to the initiation of proper immune response to environmental insults. 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. A compromised T cell tolerance was noted in Tslpr KO adult colon, which was exacerbated by anti–PD-1 and anti–CTLA-4 therapy. The lethal colitis was rescued by parabiosis between Rag1 KOTslpr KO and Rag1 KO animals and wild-type dendritic cells (DCs) suppressed CD4 + T cell–induced colitis in Rag1 KOTslpr KO mice. CD4 + T cell expansion in Rag1 KOTslpr KO mice was dependent on the gut microbiome. Endogenous TSLP signaling was required for reduced CD4 + T cell proliferation, Treg differentiation, and homeostatic cytokine production. Surprisingly, incoming CD4 + T cells induced lethal colitis in adult Rag1-knockout animals that lacked the TSLP receptor (Rag1 KOTslpr KO). 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. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic function. Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy.
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