Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity

• Published in: Nature (London) Vol. 623; no. 7989; pp. 1044 - 1052
• Main Authors: Malik, Ankit, Sharma, Deepika, Aguirre-Gamboa, Raúl, McGrath, Shaina, Zabala, Sarah, Weber, Christopher, Jabri, Bana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-11-2023; Nature Publishing Group
• Subjects: 14/63; 631/250/127/1212; 631/250/21/1566; 631/250/256/2177; 631/250/256/2515; 631/250/256/2516; 64/60; 82/1; 96/21; 96/31; 96/34; Adenosine Triphosphatases - metabolism; Adenosine triphosphate; Adenosine Triphosphate - metabolism; Antigen Presentation; Antigens; ATP; Autoantigens; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Colitis; Colitis - immunology; Colitis - pathology; Colitis - prevention & control; Colon - cytology; Colon - immunology; Colon - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; CRISPR; Cytokines; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelium; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Granulocytes; Humanities and Social Sciences; Immunity (Disease); In vivo methods and tests; Infections; Inflammasomes; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammatory bowel disease; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-1alpha - immunology; Interleukin-1beta - immunology; Interleukins; Kinases; Leukocytes (granulocytic); Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; Major histocompatibility complex; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pathogens; Science; Science (multidisciplinary); T cell receptors; γ-Interferon
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06721-1

All nucleated cells express major histocompatibility complex I and interferon‐γ (IFNγ) receptor
1
, 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.
IFNγ signalling in epithelial cells promotes antigen presentation that confers intra-epithelial T cells the ability to limit extracellular ATP and consequent NLRP3 inflammasome activation, controlling pathogenic transformation of CD4
+
T cells that promotes colitis and colorectal cancer in mouse models.