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TSLP/dendritic cell axis promotes CD4+ T cell tolerance to the gut microbiome
Jonathan L. Messerschmidt, … , Kaitlin E. Dempsey, Shadmehr Demehri
Jonathan L. Messerschmidt, … , Kaitlin E. Dempsey, Shadmehr Demehri
Published July 10, 2023
Citation Information: JCI Insight. 2023;8(13):e160690. https://doi.org/10.1172/jci.insight.160690.
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Research Article Gastroenterology Immunology

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

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Abstract

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.

Authors

Jonathan L. Messerschmidt, Marjan Azin, Kaitlin E. Dempsey, Shadmehr Demehri

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Figure 4

TSLP signaling in circulating cells suppresses CD4+ T cell expansion in the colon.

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TSLP signaling in circulating cells suppresses CD4+ T cell expansion in ...
(A) Diagram of parabiosis between Rag1KOTslprKO and Rag1KO mice. Three weeks after successful surgery, the Rag1KOTslprKO mouse (if present in each pair) was given a total dose of 4 million purified naive WT CD4+CD25– T cells i.v. (2 million/mouse). The animals were harvested at the moribund state or on day 15 after T cell transfer. (B) Representative colon H&E staining of Rag1KOTslprKO + Rag1KO, Rag1KO + Rag1KO, and Rag1KOTslprKO + Rag1KOTslprKO parabiotic pairs. Note the abundance of goblet cells in Rag1KOTslprKO + Rag1KO and Rag1KO + Rag1KO pairs, while Rag1KOTslprKO + Rag1KOTslprKO pairs have severe mucosal inflammation, crypt abscess formation, goblet cell loss, crypt distortion, and epithelial hyperplasia. Scale bars: 50 μm. (C) Colitis scoring of Rag1KOTslprKO + Rag1KO (n = 3 pairs), Rag1KO + Rag1KO (n = 2 pairs), and Rag1KOTslprKO + Rag1KOTslprKO (n = 2 pairs) parabiotic pairs. Fisher’s exact test. (D) Representative CD3/CD4 staining of colons from Rag1KOTslprKO + Rag1KO, Rag1KO + Rag1KO, and Rag1KOTslprKO + Rag1KOTslprKO parabiotic pairs. Scale bars: 50 μm. (E) CD4+ T cell counts in colon sections from Rag1KOTslprKO + Rag1KO (n = 3 pairs), Rag1KO + Rag1KO (n = 2 pairs), and Rag1KOTslprKO + Rag1KOTslprKO (n = 2 pairs) parabiotic pairs. CD3+CD4+ mucosal T cells were counted in 10 randomly selected HPFs per mouse at the end of the study. Each dot represents 1 HPF; bar graph shows mean + SD. **P < 0.01; ****P < 0.0001 by ordinary 1-way ANOVA. NS, not significant.

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