Pro-inflammatory intestinal Th17-cells are tissue-resident, accumulate in the epithelia in Crohn’s disease, and predict unresponsiveness to vedolizumab

We recently identified a population of pro-inflammatory intestinal CCR5+Th17-cells (proinflammatory Th17, pTh17) associated with intestinal inflammation in Crohn's Disease (CD) and activated by CD-associated adherent-invasive Escherichia coli. Here, we report that intestinal pTh17-cells in CD expressed genes characteristic of tissue-resident memory T-cells (TRM). They expressed high levels of CD69 and CD103 on the cell surface and accumulated in the intraepithelial lymphocyte (IEL) compartment in CD. Consistently, single T-cell RNA sequencing in CD unveiled that intraepithelial Th17-cells displayed a gene signature of activated pTh17-cells.In peripheral blood, pTh17-cells with gut-homing potential were hardly detectable. Conversely, conventional CCR5-Th17-cells ("cTh17") were present and expressed increased levels of alpha 4 beta 7-integrin in the blood of IBD patients. Consistently, intestinal cTh17-cells were reduced after treatment with vedolizumab, which blocks alpha 4 beta 7-integrin-mediated gut-homing of lymphocytes. Importantly, unresponsiveness to vedolizumab in CD was associated with increased frequencies of preexisting intestinal pTh17-cells with high sensitivity and specificity. We conclude that intestinal pTh17-cells are tissue-resident cells, which could be generated from circulating cTh17 precursor cells in the gut. Moreover, our findings are consistent with a key pathogenic role of intraepithelial Th17-cells in CD and suggest that monitoring intestinal pTh17-cells may predict unresponsiveness to vedolizumab.