An Intestinal Th17 Subset is Associated with Inflammation in Crohn’s Disease and Activated by Adherent-invasive Escherichia coli

• Published in: Journal of Crohn's and colitis 2023-12, Vol.17 (12), p.1988-2001
• Main Authors: Paroni, Moira, Leccese, Gabriella, Ranzani, Valeria, Moschetti, Giorgia, Chiara, Matteo, Perillo, Federica, Ferri, Sara, Clemente, Francesca, Noviello, Daniele, Conforti, Francesco Simone, Ferrero, Stefano, Karnani, Bhavna, Bosotti, Roberto, Vasco, Chiara, Curti, Serena, Crosti, Maria Cristina, Gruarin, Paola, Rossetti, Grazisa, Conte, Maria Pia, Vecchi, Maurizio, Pagani, Massimiliano, Landini, Paolo, Facciotti, Federica, Abrignani, Sergio, Caprioli, Flavio, Geginat, Jens
• Format: Article
• Language: English
• Subjects: Bacterial Adhesion; Crohn Disease - pathology; Escherichia coli; Escherichia coli Infections - complications; Escherichia coli Infections - pathology; Humans; Inflammation - pathology; Interleukin-23; Intestinal Mucosa - pathology; Intestines - pathology; Original; Th17 Cells - pathology; Tumor Necrosis Factor Inhibitors
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjad119

Abstract IFNγ-producing ex-Th17 cells [‘Th1/17’] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of patients with Crohn’s disease [CD]. Human Th17 cells expressing CCR5 [‘pTh17’] co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17 cells. pTh17 cells, but not Th1/17 cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5[-]Th17 cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17 cells in the intestine. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli [AIEC], but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from dendritic cells [DC]. Intestinal CCR5+Th1/17 cells responded instead to cytomegalovirus and were reduced in ulcerative colitis [UC], suggesting an unexpected protective role. In conclusion, we identified an IL-23–inducible subset of human intestinal Th17 cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role.