IFNγ-Stimulated B Cells Inhibit T Follicular Helper Cells and Protect Against Atherosclerosis

Abstract

B and T cells are interconnected in the T follicular helper-germinal center B cell (T_FH-GC B cell) axis, which is hyperactive during atherosclerosis development and loss of control along this axis results in exacerbated atherosclerosis. Inhibition of the T_FH-GC B cell axis can be achieved by providing negative co-stimulation to T_FH cells through the PD-1/PD-L1 pathway. Therefore, we investigated a novel therapeutic strategy using PD-L1-expressing B cells to inhibit atherosclerosis. We found that IFNγ-stimulated B cells significantly enhanced PD-L1 expression and limited T_FH cell development. To determine whether IFNγ-B cells can reduce collar-induced atherosclerosis, apoE ^-/- mice fed a Western-type diet were treated with PBS, B cells or IFNγ-B cells for a total of 5 weeks following collar placement. IFNγ-B cells significantly increased PD-L1^hi GC B cells and reduced plasmablasts. Interestingly, IFNγ-B cells-treated mice show increased atheroprotective Tregs and T cell-derived IL-10. In line with these findings, we observed a significant reduction in total lesion volume in carotid arteries of IFNγ-B cells-treated mice compared to PBS-treated mice and a similar trend was observed compared to B cell-treated mice. In conclusion, our data show that IFNγ-stimulated B cells strongly upregulate PD-L1, inhibit T_FH cell responses and protect against atherosclerosis.

Keywords: B cells; PD-L1; atherosclerosis; cardiovascular disease; interferon-gamma.