An intestinal Th17 subset is associated with inflammation in Crohn's Disease and activated by adhere

An intestinal Th17 subset is associated with inflammation in Crohn's Disease and activated by adherent-invasive Escherichia coli (AIEC)

Moira Paroni, Gabriella Leccese, Valeria Ranzani, Giorgia Moschetti, Matteo Chiara, Federica Perillo, Sara Ferri, Francesca Clemente, Daniele Noviello, Francesco Simone Conforti, Stefano Ferrero, Bhavna Karnani, Roberto Bosotti, Chiara Vasco, Serena Curti, Maria Cristina Crosti, Paola Gruarin, Grazisa Rossetti, Maria Pia Conte, Maurizio Vecchi, Massimiliano Pagani, Paolo Landini, Federica Facciotti, Sergio Abrignani, Flavio Caprioli, Jens Geginat

Published in July 2023, Journal of Crohn's & colitis

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 characterized 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 DC. Intestinal CCR5 +Th1/17-cells responded instead to Cytomegalovirus and were reduced in 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.