Gut-homing and intestinal TIGITnegCD38+ 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.

Abstract

CD4⁺ memory T cell (T_M) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of T_M regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38⁺T_M express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT⁺CD38⁺T_M have regulatory function while TIGIT^negCD38⁺T_M are enriched in IFN-γ-producing cells. We hypothesized TIGIT^negCD38⁺T_M are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT⁺CD38⁺T_M in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGIT^negCD38⁺T_M frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGIT^negCD38⁺T_M were highly enriched in HLA-DR⁺ and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated T_M identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGIT^negCD38⁺ phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGIT^negCD38⁺T_M than TIGIT⁺CD38⁺T_M, 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 TIGIT^negCD38⁺T_M and causes more severe disease.