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

Hidde Douna,Frank H Schaftenaar,Ilze Bot,Christoph J Binder,Amanda C Foks,J De Mol,Jacob Amersfoort,Bianca E Suur,Mara J Kroner,Mate G Kiss,Johan Kuiper,Gijs H M Van Puijvelde

doi:10.3389/fcvm.2022.781436

Abstract

B and T cells are interconnected in the T follicular helper—germinal center B cell (TFH-GC B cell) axis, which is hyperactive during atherosclerosis development and loss of control along this axis results in exacerbated atherosclerosis. Inhibition of the TFH–GC B cell axis can be achieved by providing negative co-stimulation to TFH 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 TFH 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-L1hi 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 TFH cell responses and protect against atherosclerosis.

Highlights

Cardiovascular disease (CVD) remains a major global health problem despite great developments in diagnosis and treatment
Whereas we observed no significant differences in PD-L1hi B cells between chow fed apoE−/− mice and apoE−/− mice fed a Western-type diet (WTD) for 2 weeks, longer administration of WTD increases the percentage of PD-L1hi B cells, in line with previous findings
Direct depletion of TFH cells in ldlr−/− mice resulted in a reduction of atherosclerosis [14], and loss of control on the TFH–GC B axis by depletion of marginal zone (MZ) B cells [13] or CD8+ regulatory T cells [12] aggravated atherosclerosis

Summary

Introduction

Cardiovascular disease (CVD) remains a major global health problem despite great developments in diagnosis and treatment. The underlying cause for CVD is atherosclerosis, which is a chronic autoimmune-like disease and is characterized by the formation of lipid-rich lesions in the arteries. The current available treatments are aimed at lipid lowering and lead to a 25–30% relative risk reduction, indicative of an urgent need for novel disease-modifying drugs. In the last decade, accumulating evidence identified the immune system as a major contributor to the pathology of atherosclerosis [1]. For this reason, considerable effort has been devoted to restore the dysregulation of the immune system and inflammatory pathways in atherosclerosis.

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Conclusion