An intestinal Th17 subset is associated with inflammation in crohn's disease and activated by adherent-invasive Escherichia coli (aiec)

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.