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P038 Microbial regulation of T-cell fate towards regulatory profiles during T-cell transfer induced colitis

Machicote, A.(1);Pelczar, P.(1);Nawrocki , M.(1);Fazio, A.(1);Liu , B.(1);Kopplin, L.(2);Wende, M.(3);Indenbirken, D.(4);Pabst, O.(2);Strowig, T.(3);Gagliani, N.(5);Huber, S.(1);

(1)Zentrum für Innere Medizin Universitätsklinikum Hamburg-Eppendorf, I. Medizinische Klinik und Poliklinik, Hamburg, Germany;(2)Institute of Molecular Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;(3)Helmholtz Centre for Infection Research, Department of Microbial Immune Regulation, Braunschweig, Germany;(4)Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;(5)Zentrum für Operative Medizin, Department of General- Visceral and Thoracic Surgery, Hamburg, Germany

Background

During Inflammatory Bowel Diseases (IBD), CD4+ effector T cells are main mediators of the tissue damage. Among them, Th17 cells strongly contribute to the inflammatory response. Interestingly, our lab previously showed that Th17 cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces controlling the plasticity of T cells during IBD remain largely unknown. Our aim is to understand, how CD4+ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile during IBD. It is currently known that both Th17 and Foxp3 Treg cells can recognize microbiota-derived antigens and that changes in the microbiota are commonly observed in IBD. We hypothesize that the microbiota is a key candidate to modulate T-cell plasticity. 

Methods

T-cell transfer mouse IBD model was performed by transferring CD4+ naïve T-cells into Rag1-/- receptors. To study Th17 T-cell plasticity, we used as donors IL-17A Fate-mapping mice. These mice comprise of an IL-17ACRE/R26fl/fl YFP construct where the cells that previously expressed IL-17A turn into YFP+ cells. Ciprofloxacin and metronidazole, two antibiotics commonly given to IBD patients, were used to treat the mice. Stool microbiota composition was analysed longitudinally by 16S rRNA amplicon sequencing. Colitis development was evaluated by colonoscopy. CD4+ T cells were isolated from the colon and reporter expression was analysed by Flow Cytometry.

Results

After T-cell transfer colitis induction, ciprofloxacin and metronidazole treatment alleviated gut inflammation, as determined by weight loss (p=0.005), colitis score (p=0.004) and colon length (p=0.01). Antibiotic treatment increased the relative abundance of bacteria previously associated with beneficial IBD outcomes (e.g. Bifidobacterium). Interestingly, colonic CD4+ T-cells showed an increased conversion from Th17 towards a Foxp3+ Treg profile (Foxp3ExTh17) (p=0.03).

Conclusion

The conversion of CD4+ effector T cells into Treg cells is a promising approach to counteract inflammation in IBD patients. We showed that antibiotic treatment not only correlates with a relative expansion of beneficial bacteria, but perhaps most interesting, with an increased conversion of effector Th17 cells towards Foxp3+ Treg cells in the colon. Altogether, these data support the manipulation of the microbiota as a tool to revert intestinal inflammation in IBD patients.

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