Gut-homing and intestinal TIGITCD38 memory T cells acquire an IL-12-induced, ex-Th17 pathogenic phenotype in a subgroup of Crohn's disease patients with a severe disease course.

CD4 memory T cell (T) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of T regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38T express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGITCD38T have regulatory function while TIGITCD38T are enriched in IFN-γ-producing cells. We hypothesized TIGITCD38T are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGITCD38T in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGITCD38T frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGITCD38T were highly enriched in HLA-DR and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated T identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGITCD38 phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGITCD38T than TIGITCD38T, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGITCD38T and causes more severe disease.