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.