T-bet-Expressing B Cells Are Positively Associated with Crohn's Disease Activity and Support Th1 Inflammation

Abstract

Pathogenesis of Crohn's disease (CD) is thought to involve the chronic activation of T helper 1 (Th1)- and Th17-mediated inflammation, such as the production of interferon-gamma (IFN-γ) and interleukin 17 (IL-17). However, studies have also shown that although IFN-γ is required, IFN-γ-producing or T-bet-expressing Th1 cells are dispensable. We therefore examined T-bet-expressing B cells as another source of IFN-γ that potentially supported intestinal inflammation in CD patients. We found that the frequencies of T-bet-expressing B cells were significantly upregulated and abundantly present in the gut of active, but not quiescent, CD patients. The frequencies of T-bet-expressing B cells were also directly correlated with CD disease activity. These T-bet⁺ B cells were almost exclusively IgG expressing and produced significantly higher amounts of IFN-γ, IL-6, and IL-12 than IgA- and IgM-expressing T-bet^- B cells. These B cells also supported IFN-γ production of CD4⁺ T cells. T-bet expression was induced in vitro in peripheral blood B cells through the stimulation of B-cell receptor (BCR), Toll-like receptor 7 (TLR7), and IFN-γ, which resembled gut T-bet⁺ B cells in terms of elevated IFN-γ. We found that these stimulated B cells, but not unstimulated B cells, supported the IFN-γ and IL-12 production from autologous CD4⁺ T cells. In addition, in patients with higher gut T-bet⁺ B-cell percentage, a higher frequency of gut-infiltrating IFN-γ⁺ and IL-12⁺ T cells was also observed. Together, our results suggested that T-bet-expressing B cells could contribute to the intestinal Th1 inflammation in CD patients.