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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 5

TSLP signaling to DCs suppresses CD4+ T cell expansion in the colon.

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TSLP signaling to DCs suppresses CD4+ T cell expansion in the colon.
(A–...
(A–C) Flow cytometric quantification of CD11c+ myeloid DC frequency (A) and CD103+CD11c+ migratory DC frequency as a percentage of CD45+ leukocytes (B) versus CD11c+ myeloid DCs (C) in Rag1KOTslprKO (n = 5) and Rag1KO (n = 5) MLNs following adoptive transfer of naive WT CD4+CD25– T cells. Rag1KOTslprKO tissues were obtained at the moribund state and Rag1KO samples were harvested on day 15 after T cell transfer. Each dot represents 1 mouse. (D–F) Flow cytometric quantification of CD11c+ myeloid DC frequency (D) and CD103+CD11c+ migratory DC frequency as a percentage of CD45+ leukocytes (E) versus CD11c+ myeloid DCs (F) in Rag1KOTslprKO (n = 5) and Rag1KO (n = 5) colon following adoptive transfer of naive WT CD4+CD25– T cells. Rag1KOTslprKO tissues were obtained at the moribund state and Rag1KO samples were harvested on day 15 after T cell transfer. Each dot represents 1 mouse. (G) Representative H&E staining of colons from Rag1KOTslprKO mice that received WT or TslprKO DC transfer 1 day before adoptive CD4+ T cell transfer. Note the loss of goblet cells, moderate inflammation, and crypt hyperplasia in the animals given TslprKO DCs compared with those that received WT DCs before T cell transfer. Scale bars: 50 μm. (H) CD4+ T cell counts in Rag1KOTslprKO colons after the transfer of WT (n = 5) versus TslprKO (n = 5) DCs followed by an adoptive naive WT CD4+CD25– T cell transfer. CD3+CD4+ colonic T cells were quantified in 10 randomly selected HPFs per mouse at the moribund state or on day 15 after T cell transfer. Each dot represents 1 HPF; bar graphs show mean + SD. **P < 0.01; ****P < 0.0001 by unpaired, 2-tailed t test. NS, not significant.

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