Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity

Ankit Malik (), Deepika Sharma, Raúl Aguirre-Gamboa, Shaina McGrath, Sarah Zabala, Christopher Weber and Bana Jabri ()
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Ankit Malik: University of Chicago
Deepika Sharma: University of Chicago
Raúl Aguirre-Gamboa: University of Chicago
Shaina McGrath: University of Chicago
Sarah Zabala: University of Chicago
Christopher Weber: University of Chicago
Bana Jabri: University of Chicago

Nature, 2023, vol. 623, issue 7989, 1044-1052

Abstract: Abstract All nucleated cells express major histocompatibility complex I and interferon‐γ (IFNγ) receptor1, but an epithelial cell-specific function of IFNγ signalling or antigen presentation by means of major histocompatibility complex I has not been explored. We show here that on sensing IFNγ, colonic epithelial cells productively present pathogen and self-derived antigens to cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers extracellular ATPase expression in cognate intra-epithelial T cells, which limits the accumulation of extracellular adenosine triphosphate and consequent activation of the NLRP3 inflammasome in tissue macrophages. By contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated interleukin-1α and interleukin-1β production promotes a pathogenic transformation of CD4+ T cells into granulocyte–macrophage colony-stimulating-factor (GM-CSF)-producing T cells in vivo, which promotes colitis and colorectal cancer. Taken together, our study unravels critical checkpoints requiring IFNγ sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo.

Date: 2023
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DOI: 10.1038/s41586-023-06721-1

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