Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death

Abstract

AimsThe E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis.Methods and resultsThe expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb−/−Apoe−/− mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8+ T cells. Cblb−/−Apoe−/− macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8+ T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ and granzyme B production was enhanced in Cblb−/−Apoe−/− CD8+ T cells, which provoked macrophage killing. Depletion of CD8+ T cells in Cblb−/−Apoe−/− bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8+ T cells.Conclusion Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8+ T cell activation and CD8+ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.

CD8+ T Cells in Atherosclerosis

“…Genetic deletion of CBL-B entailed an increase in plaque T cells in 20 week old Apoe −/− mice, and especially in cytotoxic T cells that were resistant to apoptosis and regulatory T cell-mediated suppression. Cblb − / − Apoe − / − CD8 + T cells showed enhanced IFN-γ and granzyme B production and plaque macrophage killing, which resulted in increased lesional inflammation and a significant increase in plaque area [ 52 ]. In this study, CD8 + T cells thus seemed to promote inflammation, the accumulation of proinflammatory Th1 cells and atherosclerosis [ 52 ], similar to findings in early atherosclerosis.…”

Exploration and Validation of Hub Genes and Pathways in the Progression of Hypoplastic Left Heart Syndrome via Weighted Gene Co-Expression Network Analysis

“…Five hub genes including Cblb, Ccl2, Edn1, Itgb3 and Map2k1 were screened for HLHS in the pink module. Cblb (Casitas B-cell lymphoma-B) is lowly expressed in plaques for human atherosclerosis, thereby leading to CD8 + T cell-induced macrophage death and accelerating atherosclerosis [32]. Our ndings revealed that Cblb expression was signi cantly down-regulated in RV HLHS not LV HLHS in comparison to controls.…”

An overview of the innate and adaptive immune system in atherosclerosis

“…254 Furthermore, a decrease in the number of CD8 + T cells by antibodies was found to decrease the severity of atherosclerosis in mice, showing the pro-atherogenic role of CD8 + T cells. 255,256 In these cells, the production of granzyme B and IFN-γ is higher than CD8 + T cells in non-atherosclerotic mice. 256 Results from a study on Ldlr −/− mice fed with high-fat diets revealed that CD8 + T cells develop atherosclerosis by regulating the level of peripheral monocytes, through production of IFN-γ.…”

“…255,256 In these cells, the production of granzyme B and IFN-γ is higher than CD8 + T cells in non-atherosclerotic mice. 256 Results from a study on Ldlr −/− mice fed with high-fat diets revealed that CD8 + T cells develop atherosclerosis by regulating the level of peripheral monocytes, through production of IFN-γ. 255 However, findings from another study revealed that IFN-γ produced by CD8 + T cells has no role in atherosclerosis in Apoe −/− mice fed with highfat diet.…”