Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8 ⁺ Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development

Abstract

Background-The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. Methods and Results-Here, we analyzed the contribution of Qa-1-restricted CD8 + regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8 + regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. Conclusions-This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenicand that CD8 + regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach.

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

“…FoxP3þ CD4 cells constitute a Treg population that is atheroprotective, particularly in experimental settings. Recent data have suggested that there are CD8þ T cells with an immunosuppressive capacity 24 and that such CD8þ Tregs influence atherosclerosis. 24 To shed light on these mechanisms, PBMCs from patients undergoing CEA were used for in vitro analysis.…”

“…Recent data have suggested that there are CD8þ T cells with an immunosuppressive capacity 24 and that such CD8þ Tregs influence atherosclerosis. 24 To shed light on these mechanisms, PBMCs from patients undergoing CEA were used for in vitro analysis. However, the in vitro system with purified CD4 T cells, CD8 T cells or macrophages did not at all mount the same strong response in IL-10 secretion as that observed in the plaque tissues examined in the ex vivo protocols.…”

Once Upon a Time: The Adaptive Immune Response in Atherosclerosis—a Fairy Tale No More

“…However, the observation of TLOs in the human adventitia of atherosclerotic aorta (10,33), as well as in the adventitia of atherosclerotic mice (8,9), suggests that an adaptive immune response could be mounted within the arterial wall in the adventitia (Figure 1). Indeed, GC B cells, plasma cells and Tfh cells can be found in adventitial TLOs of atherosclerotic ApoE -/-mice, arguing that a humoral immune response might be generated locally (8,29). We recently confirmed that this also is the case in human vascular disease, as the adventitia from atherosclerotic abdominal aortic aneurysms displays TLOs containing Tfh, GC B cells and plasma cells and releases antibodies (29).…”

“…Indeed, GC B cells, plasma cells and Tfh cells can be found in adventitial TLOs of atherosclerotic ApoE -/-mice, arguing that a humoral immune response might be generated locally (8,29). We recently confirmed that this also is the case in human vascular disease, as the adventitia from atherosclerotic abdominal aortic aneurysms displays TLOs containing Tfh, GC B cells and plasma cells and releases antibodies (29). The existence of this lymphoid neogenesis in the aorta might impair the efficiency of therapeutic strategies targeting the immune system, such as B2 cell depletion, as it occurs in other chronic inflammatory settings such as chronic graft rejection.…”

“…Interestingly, in line with the proatherogenic role of B2 cells, it has been suggested that rituximab (anti-CD20) can become a treatment in atherosclerosis (19,20). However, it would be important to verify that this treatment also depletes B cells from TLOs during atherosclerosis, considering that this is not the case in the context of allograft (34), and that aortic TLOs are sites of B-cell activation (29). Another strategy to impair B2 cell function would be to block their activation by Tfh cells.…”