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

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.

SUBMITTER: Chen L

PROVIDER: S-EPMC9243055 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeImmune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes.MethodsThe density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides.ResultsWe found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin's lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin's lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved.ConclusionThese data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.

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

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Dataset Information

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

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OmicsDI is part of the ELIXIR infrastructure

Tweets

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