Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn´s Disease
CHIAROLLA C. 1, SCHULZ A. 2, MEIR M. 3, REU-HOFER S. 1, ROMERO-OLMEDO A. 4, FALCONE V. 5, BÜTTNER-HEROLD M. 6, PRELOG M. 7, ROSENWALD A. 1,8, HENGEL H. 5, LOHOFF M. 4, CHANG H. 9, SCHLEGEL N. 3, MEI H. 2, BERBERICH-SIEBELT F. 1
1 Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany; 2 Mass Cytometry Lab, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany; 3 Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany; 4 Institute of Medical Microbiology and Hospital Hygiene, Philipps University Marburg, Marburg, Germany; 5 Institute of Virology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; 6 Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; 7 Department of Pediatrics, University Hospital Wuerzburg, Würzburg, Germany, Würzburg, Germany; 8 Comprehensive Cancer Centre Mainfranken, Julius-Maximilians-University Würzburg, Würzburg, Germany; 9 Schwiete Laboratory for Microbiota and Inflammation, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
A complex and tissue-specific network of cells, including T lymphocytes, maintains intestinal homeostasis. To address disease and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with Crohn’s disease (CD) and healthy donor PBMCs. We compared inflamed and not inflamed tissue areas of bowel resections. Chronic inflammation enforced activation, exhaustion, and terminal differentiation of CD4+ and CD8+ T cells and enrichment of CD4+Foxp3+ cells (Tregs) in the inflamed intestine. However, tissue-repairing Tregs decreased, while enigmatic rare Foxp3+ T-cell subsets appeared upon inflammation. In vitro assays revealed that those subsets, e.g. CD4+Foxp3+HLA–DR+TIGIT– and CD4+Foxp3+CD56+, express pro-inflammatory IFN-γ. At the same time, some T-conventional (Tcon) cells acquired innateness. In the blood of CD patients, not well-studied CD4+ and CD8+ subsets of CD16+CCR6+CD127+ T cells appeared anew, a phenotype reproducible by incubation of healthy blood T cells with IBD patients’ blood plasma. Together, these findings suggest a bias towards innate-like pro-inflammatory Tregs and innate-like Tcon, which act with less specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.