Work

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

Year: 2024

Type: article

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 neg CD38 + T M are enriched in IFN-γ-producing cells. We hypothesized TIGIT neg CD38 + 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 neg CD38 + 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 neg CD38 + 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 neg CD38 + phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGIT neg CD38 + 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 neg CD38 + T M and causes more severe disease.

Source: Mucosal Immunology

DOI: 10.1016/j.mucimm.2024.11.008