DOP32 CD226+TIGITneg expression identifies pathogenic inflammatory CD4+ memory T cells in severe Crohn’s Disease patients, opening up opportunities for patient-tailored treatment strategies

Abstract

Abstract Background CD4+ memory T cells (Tmem) drive chronicity of inflammation in Crohn’s disease (CD) and ulcerative colitis (UC). Treatments specifically targeting T cells effectively induce disease remission. However, due to disease heterogeneity and possibly variation in the Tmem response, not all patients achieve or maintain remission. As such, strategies are needed to identify and monitor the therapeutic target, i.e. the inflammatory Tmem response, in individual patients. Monitoring has been hampered by the large variety in both protective regulatory and pathogenic inflammatory Tmem phenotypes, thus, common denominators need to be identified to distinguish all inflammatory from all regulatory intestinal Tmem populations in individual patients. We have shown that the coinhibitory receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a common denominator identifying regulatory gut-homing Tmem. TIGIT shares its ligands with the costimulatory receptor CD226. While TIGIT ligation inhibits Tmem responses, CD226 engagement enhances Tmem activity. We hypothesize that TIGIT and CD226 differentiate the protective regulatory from the pathogenic inflammatory intestinal Tmem in individual IBD patients. Methods We studied CD38+CD62Lneg gut-homing Tmem in blood of therapy-naive pediatric IBD patients (CD n=59; UC n=32; IBD negative controls (IBDneg) n=24). Results In a subgroup of CD, but not UC patients, frequencies of regulatory TIGIT+ gut-homing Tmem at diagnosis were strongly reduced compared to IBDneg. Of these CD patients with low TIGIT frequencies, a significantly higher proportion had severe disease, defined as failing to achieve remission after 6 months or having a disease relapse within 1 year, compared to CD with normal TIGIT frequencies. As TIGIT is a common denominator for regulatory cells, we hypothesized that gut-homing Tmem without TIGIT (TIGITneg) contained inflammatory Tmem. Indeed, in CD, the TIGITneg Tmem population contained increased frequencies of pathogenic IFNg+IL-17+-double-producing cells compared to IBDneg. As TIGIT and CD226 frequencies inversely correlated (R=-0.78, p=4.8e-05) in CD patients, we assessed whether additional monitoring of CD226 could be used to more precisely identify and monitor inflammatory Tmem in CD. As anticipated, TIGITnegCD226+ gut-homing Tmem frequencies significantly increased in CD patients compared to UC patients and IBDneg. TIGITnegCD226+ Tmem were more proliferative and more activated compared to IBDneg, indicating increased inflammatory function. Conclusion These data establish that TIGIT and CD226 can be used to enumerate and differentiate the protective regulatory from the pathogenic inflammatory gut-homing Tmem in individual IBD patients, and to identify patients with severe disease.