JCI Insight. 2023 Jul 10;8(13):e160690. doi: 10.1172/jci.insight.160690.
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 (Rag1KOTslprKO). Endogenous TSLP signaling was required for reduced CD4+ T cell proliferation, Treg differentiation, and homeostatic cytokine production. CD4+ T cell expansion in Rag1KOTslprKO mice was dependent on the gut microbiome. The lethal colitis was rescued by parabiosis between Rag1KOTslprKO and Rag1KO animals and wild-type dendritic cells (DCs) suppressed CD4+ T cell-induced colitis in Rag1KOTslprKO mice. A compromised T cell tolerance was noted in TslprKO 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.
胸腺基质淋巴细胞生成素（TSLP）过表达与特应性广泛相关。然而，TSLP 在正常的屏障器官中表达，提示其具有稳态功能。为了确定 TSLP 在屏障部位的功能，我们研究了内源性 TSLP 信号对成年小鼠中 CD4+T 细胞稳态扩增的影响。令人惊讶的是，内源性 TSLP 信号对于 Rag1 敲除（Rag1KO）动物中 CD4+T 细胞的增殖、Treg 分化和稳态细胞因子产生的减少是必需的。Rag1KOTslprKO 小鼠中的 CD4+T 细胞扩增依赖于肠道微生物组。Rag1KOTslprKO 和 Rag1KO 动物之间的联体和野生型树突状细胞（DC）挽救了 Rag1KOTslprKO 小鼠的致死性结肠炎。在 TslprKO 成年结肠中注意到 T 细胞耐受受损，抗 PD-1 和抗 CTLA-4 治疗使其恶化。这些结果揭示了结肠中 TSLP 和 DC 之间的一个关键外周耐受轴，该轴阻止 CD4+T 细胞针对共生肠道微生物组的激活。
