T‐bet interferes with PD‐1/PD‐L1‐mediated suppression of CD4+ T cell inflammation and survival in Crohn's disease

Abstract Pathogenic inflammation mediated by overactive type 1 helper T cell (Th1) responses could exacerbate and perpetuate Crohn's disease. Programmed death (PD)‐1 and its ligand PD‐L1 pathway could be upregulated to suppress inflammation. We wondered why this pathway is ineffective at suppressing pathogenic Th1 inflammation in Crohn's disease patients. Here, we found that overexpression of T‐bet via transfection significantly reduced the expression of PD‐1. PD‐L1 was capable of suppression proinflammatory CD4 + T cells, but T‐bet transfection significantly reduced the susceptibility of CD4 + T cells toward PD‐L1‐mediated suppression, evidenced by the observations that at low PD‐L1 concentration T‐bet transfected and mock transfected CD4 + T cells presented comparable IL‐2 production, but at high PD‐L1 concentration, T‐bet transfected CD4 + T cells presented significantly higher IL‐2 than mock transfected CD4 + T cells. PD‐L1 could significantly reduce the survival of CD4 + T cells from Crohn's disease patients, but interestingly, in the absence of PD‐L1, the survival was better in mock transfected CD4 + T cells, while in the presence of PD‐L1, the survival was better in T‐bet transfected CD4 + T cells. Crohn's disease patients with greater severity presented higher T‐bet expression and lower PD‐1 expression in CD4 + T cells, demonstrating an association between T‐bet expression and disease progression. We also discovered that stimulation with bacterial antigens could upregulate the expression of T‐bet. Together, this study demonstrated that T‐bet overexpression could interfere with PD‐1/PD‐L1‐mediated suppression of CD4 + T cell inflammation and survival, and potentially contributed to the development and persistence of Crohn's disease.