P045 TIGIT expression differentiates regulatory from inflammatory Th1* gut-homing effector CD4+ T cells in inflammatory bowel disease patients
Heredia, M.(1);Costes, L.M.M.(1);Tindemans, I.(1);Aardoom, M.A.(2);Klomberg, R.C.W.(2);Kemos, P.(3);Joosse, M.E.(1);van Haaften, D.H.(1);Tuk, B.(1);Ruemmele, F.(4);Croft, N.M.(3);Escher, J.C.(2);de Ridder, L.(2);Samsom, J.N.(1);
(1)Erasmus University Medical Center-Sophia Children’s Hospital, Laboratory of Pediatric Gastroenterology, 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)Hôpital Necker-Enfants Malades- Institut Imagine- AP-HP- Université de Paris, Pediatric Gastroenterology, Paris, France;
Background
Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal infiltration of pathogenic effector CD4+ T cells. The defects driving loss of T-cell regulation vary between patients and remain undefined. Previously, we have shown that in human intestine, 20-40% of effector (CD62LnegCD4+) T cells express TIGIT (T cell immunoglobulin and ITIM domain), an inhibitory receptor modulating dendritic cell and T-cell function. TIGIT expression is enriched in circulating gut-homing CD38+ effector T cells in healthy controls while in a subgroup of IBD patients with active intestinal inflammation, frequencies of inhibitory TIGIT+CD38+ effector T cells are decreased and associated with earlier relapse of disease. Here we hypothesized that gut-homing effector T cells lacking TIGIT (TIGITneg) are pathogenic mediators of intestinal inflammation in IBD and assessed whether patients with low frequencies have a distinctive disease immunotype.
Methods
In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=50; UC: n=25), patients with suspicion of IBD but negative diagnosis (n=17) and age-matched healthy controls (HC: n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood, collected plasma at diagnosis and during therapy and phenotyped intestinal T cells.
Results
At diagnosis, 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and HC. CD patients with reduced frequencies of inhibitory TIGIT+CD38+ effector T cells had higher plasma IFN-γ concentrations and 53% of them experienced a disease relapse by 1 year versus 25% for CD patients with normal TIGIT+CD38+effector frequencies. In keeping with our hypothesis that TIGITneg gut-homing effector T cells are pathogenic, absence of TIGIT expression identified CD38+ effector T cells enriched in recent proliferation and having high expression of chemokine receptors associated with inflammatory non-classical T helper-1 IFNγhighIL-17Alow producing (Th1*) cells. Moreover, intestinal TIGITnegCD4+ T cells of CD patients contained higher frequencies of IFNγ and IL-17A producing cells than TIGIT+CD4+ T cells. In order to identify the factors that drive differentiation of the pathogenic Th1* cells, inhibitory TIGIT+CD38+ effector T cells from HC were exposed to an array of IBD-associated cytokines in vitro. Only IL-12p70, a known driver of IFNγ, could convert inhibitory TIGIT+CD38+ effector T cells into their TIGITneg proinflammatory counterpart.
Conclusion
We identify TIGITneg gut-homing effector T cells, enriched in Th1* cells, as potential drivers of intestinal inflammation in a subgroup of CD, but not UC patients, with a more severe disease course.