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

Lili Chen, Zhengxiang He, Bernardo S. Reis, Jesse D. Gelles, Jerry Edward Chipuk, Adrian T. Ting, Julie A. Spicer, Joseph A. Trapani, Glaucia C. Furtado, Sergio A. Lira

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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)-γ-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-γ. 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-γ constrained IL-23- and Red 40-induced colitis development, and blockade of IFN-γ 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-γ+ cytotoxic CD4+ T cells as a new potential therapeutic target for colitis.

Original languageEnglish
Pages (from-to)777-790
Number of pages14
JournalCellular and Molecular Immunology
Volume19
Issue number7
DOIs
StatePublished - Jul 2022

Keywords

  • Allura Red; IL23; Cytotoxic CD4 T cells; CD4 CTL; Inflammation; Epithelium damage; Colitis

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