IFN-gamma+ cytotoxic CD4+ T lymphocytes are involved in the pathogenesis of colitis induced by IL-23 and the food colorant Red 40

Chen, L; He, Z; Reis, BS; Gelles, JD; Chipuk, JE; Ting, AT; Spicer, JA; Trapani, JA; Furtado, GC; Lira, SA

Author(s): Chen, L; He, Z; Reis, BS; Gelles, JD; Chipuk, JE; Ting, AT; Spicer, JA; Trapani, JA; Furtado, GC; Lira, SA;
Details: Publication Year 2022-07,Volume 19,Issue #7,Page 777-790
Journal Title: Cellular & Molecular Immunology
Publication Type: Research article
Abstract: The food colorant Red 40 is an environmental risk factor for colitis development in mice with increased expression of interleukin (IL)-23. This immune response is mediated by CD4(+) T cells, but mechanistic insights into how these CD4(+) T cells trigger and perpetuate colitis have remained elusive. Here, using single-cell transcriptomic analysis, we found that several CD4(+) T-cell subsets are present in the intestines of colitic mice, including an interferon (IFN)-gamma-producing subset. In vivo challenge of primed mice with Red 40 promoted rapid activation of CD4(+) T cells and caused marked intestinal epithelial cell (IEC) apoptosis that was attenuated by depletion of CD4(+) cells and blockade of IFN-gamma. Ex vivo experiments showed that intestinal CD4(+) T cells from colitic mice directly promoted apoptosis of IECs and intestinal enteroids. CD4(+) T cell-mediated cytotoxicity was contact-dependent and required FasL, which promoted caspase-dependent cell death in target IECs. Genetic ablation of IFN-gamma constrained IL-23- and Red 40-induced colitis development, and blockade of IFN-gamma inhibited epithelial cell death in vivo. These results advance the understanding of the mechanisms regulating colitis development caused by IL-23 and food colorants and identify IFN-gamma(+) cytotoxic CD4(+) T cells as a new potential therapeutic target for colitis.
Keywords: Animals; *CD4-Positive T-Lymphocytes/immunology; *Colitis/chemically induced/immunology; *Food Coloring Agents/adverse effects; Interferon-gamma/metabolism; *Interleukin-23/adverse effects; Mice; Mice, Inbred C57BL; Allura Red; IL23; Cytotoxic CD4+ T cells; CD4+ CTL; Inflammation; Epithelium; damage; Colitis
Department(s): Laboratory Research
PubMed ID: 35468944
Publisher's Version: https://doi.org/10.1038/s41423-022-00864-3
Open Access at Publisher's Site: https://doi.org/10.1038/s41423-022-00864-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2024-10-16 03:59:23