Differential Pathogenic Th17 Profile in Mesenteric Lymph Nodes of Crohn's Disease and Ulcerative Colitis Patients

Abstract

The drug targets IL23 and IL12 regulate pathogenicity and plasticity of intestinal Th17 cells in Crohn's disease (CD) and ulcerative colitis (UC), the two most common inflammatory bowel diseases (IBD). However, studies examining Th17 dysregulation in mesenteric lymph nodes (mLNs) of these patients are rare. We showed that in mLNs, CD could be distinguished from UC by increased frequencies of CCR6⁺CXCR3^-RORγ⁺Tbet^-CD4⁺ (Th17) memory T cells enriched in CD62L^low effector memory T cells (T_EM), and their differentially expressed molecular profile. Th17 T_EM cells (expressing <i>IL17A, IL17F, RORC</i>, and <i>STAT3</i>) displayed a higher pathogenic/cytotoxic (<i>IL23R, IL18RAP</i>, and <i>GZMB, CD160, PRF1</i>) gene signature in CD relative to UC, while non-pathogenic/regulatory genes (<i>IL9, FOXP3, CTLA4</i>) were more elevated in UC. In both CD and UC, IL12 but not IL23, augmented IFNγ expression in Th17 T_EM and switched their molecular profile toward an ex-Th17 (Th1^*)-biased transcriptomic signature (increased <i>IFNG</i>, and decreased <i>TCF7, IL17A</i>), suggesting that Th17 plasticity occurs in mLNs before their recruitment to inflamed colon. We propose that differences observed between Th17 cell frequencies and their molecular profile in CD and UC might have implications in understanding disease pathogenesis, and thus, therapeutic management of patients with IBD.