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 (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.

Atherosclerosis and Alzheimer’s Disease Interconnection: Inflammation, Aβ and More

“…In general, the immune system plays a crucial role in atherogenesis, generating a distinct and complicated immune response that could impact the progression of other disorders related to atherosclerosis. Here we present evidence for atherosclerosis involvement in facilitating AD and describe potential processes by which an exceptional immune response generated during atherogenesis could impact AD development (Douna et al, 2022).…”

T-Cell/B-Cell Interactions in Atherosclerosis

“…83 Nevertheless, as explained above, others have shown an atheroprotective role upregulating PDL1 in B2 cells. 64 Thus its role in different B-cell subsets should be addressed. GC-localized T FH cells eventually express IL-4, which synergizes with IL-21 to promote antibody responses.…”

“…The protective role of PDL1 hi B cells was subsequently corroborated through a different mechanism. 64 Adoptive transfer of IFNγ (interferon-γ)-stimulated B cells that populated both MZ and GC B-cell compartments significantly decreased T FH and PCs, without altering antibody levels and increased T REG cells, leading to reduced atherosclerosis. This indicates IFNγ-stimulated B cells may alter T FH cell numbers but not their function while inducing atheroprotective T REG differentiation.…”

“… 83 Nevertheless, as explained above, others have shown an atheroprotective role upregulating PDL1 in B2 cells. 64 Thus its role in different B-cell subsets should be addressed.…”