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P012 Low frequencies of circulating inhibitory TIGIT+CD38+ effector T cells identify an immunologically distinct subgroup of pediatric patients with severe Crohn's disease

Heredia, M.(1);Costes, L.(1);Tindemans, I.(1);Aardoom, M.(2);Klomberg, R.(2);Kemos, P.(3);Joosse, M..(1);van Haaften, D.(1);Tuk, B.(1);Ruemmele, F.(4);Croft, N.(3);Escher, J.(2);de Ridder, L.(2);Samsom, J.(1);

(1)Erasmus University Medical Center-Sophia Children’s Hospital, Laboratory of Pediatrics- division Gastroenterology and Nutrition, Rotterdam, The Netherlands;(2)Erasmus University Medical Center-Sophia Children’s Hospital, Pediatric Gastroenterology, Rotterdam, The Netherlands;(3)Blizard Institute- Queen Mary University of London, Centre for Immunobiology, London, United Kingdom;(4)Necker-Enfants Malades University Hospital- Institut Imagine- AP-HP- Université de Paris, Pediatric Gastroenterology, Paris, France

Background

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a T cell driven intestinal inflammation. Current T cell suppressive therapeutic regimens are moderately successful due to a large clinical heterogeneity amongst patients. Detailed understanding of aberrant inflammatory and inhibitory T-cell responses in individual patients is lacking. Previously, we have shown that, in healthy individuals, 40% of peripheral blood CD38+ (CD62LnegCD4+) effector T cells, which are enriched for intestinal antigen specificity, express the inhibitory molecule T cell immunoglobulin and ITIM domain (TIGIT).  TIGIT+CD38+ effector T cells have a regulatory function, produce IL-10 and express multiple co-inhibitory receptors. Conversely, TIGITnegCD38+ effector T cells are enriched in inflammatory IFN-γ producing cells. In a small cohort of pediatric-onset IBD patients, low frequencies of TIGIT+CD38+ effector T cells were associated with a reduced duration of clinical remission. We hypothesize that a subgroup of IBD patients has reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells, reflecting a distinct pathogenesis associated with a more severe disease course.

Methods

In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=37; UC: n=16), patients with suspicion of IBD but negative diagnosis (n=12) and age-matched healthy controls (n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood and collected plasma at diagnosis and during immunosuppressive therapy.

Results

At diagnosis, approximately 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and age-matched controls. CD patients with low frequencies of TIGIT+CD38+ effector T cells at diagnosis needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF treatment within 1 year versus 38% for patients with normal frequencies of TIGIT+CD38+ effector T cells. Inflammatory TIGITnegCD38+ effector T cells were enriched in Ki67, reflecting recent proliferation, and expressed chemokine receptors associated with inflammatory non-classical T-helper-1 IFN-γhiIL-17lo producing cells. High frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations.

Conclusion

These results demonstrate that reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells discriminate a subgroup of pediatric CD patients with high frequencies of inflammatory IFN-γhiIL-17lo producing cells, high plasma IFN-γ concentrations, and in need of early anti-TNF treatment, possibly indicative of a distinct pathogenesis with a more severe disease course.

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