NKT Cell Hyporesponsiveness Leads to Unrestrained Accumulation of Marginal Zone B Cells in Hypercholesterolemic Apolipoprotein E–Deficient Mice

Abstract

Recently, the role of B cells in atherosclerosis has gained more attention but studies have mainly focused on B1 and follicular B cell subsets. Therefore, the contribution of marginal zone (MZ) B cells in experimental atherosclerosis remains elusive. In the current study, we examined the MZ B cell compartment in atherosclerotic apoE-deficient (apoE) mice and found that hypercholesterolemia in these mice was associated with an increased number and percentage of MZ B cells. This aberrant accumulation of MZ B cells was not associated with alterations in their development or increased proliferation but was due to decreased apoptotic cell death. This decrease in MZ B cell death in apoE mice was associated with the reduced capacity of invariant NKT (iNKT) cells to produce IFN-γ and IL-4 after activation. Lowering cholesterol plasma levels with ezetimibe in apoE mice reversed iNKT function and MZ B cell accumulation. To elucidate the mechanism whereby iNKT cells control MZ B cell accumulation in apoE mice, we performed an adoptive transfer of iNKT cells and found that only wild-type iNKT cells but not IFN-γ iNKT cells reversed MZ B cell accumulation in apoE recipient mice. Our findings reveal that lipid changes associated with atherosclerotic disease induce decreased production of IFN-γ by iNKT, which in turn leads to aberrant accumulation of MZ B cells. This study further extends the importance of iNKT cells in regulating MZ B cell compartment.

Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

“…Only a few previous studies have addressed the role of MZB cells in a hypercholesterolemic context 16,40 . MZB cell abundance increases in the spleens of hypercholesterolemic Apoe − / − mice compared to wild type animals, due in part to decreased IFNγ release by iNKT cells 40 .…”

“…Only a few previous studies have addressed the role of MZB cells in a hypercholesterolemic context 16,40 . MZB cell abundance increases in the spleens of hypercholesterolemic Apoe − / − mice compared to wild type animals, due in part to decreased IFNγ release by iNKT cells 40 . MZB cells also ingest modified LDL and mount extra-follicular antibody responses against oxidation-specific epitopes 16 In view of our findings that, in HCD-fed mice, MZB cells leave the marginal zone and interact with (pre)Tfh cells, it will be important to study the signals that instruct the MZB cells to leave the marginal zone and guide them to Tfh cells.…”

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

“…Recently iNKT‐derived IFN‐γ has been shown to induce apoptosis of marginal zone B cells, suggesting a regulatory iNKT subset. The authors implicate expansion of marginal zone B cells in relation to loss of iNKT‐derived IFN‐γ in increased atherosclerosis in long‐term high‐fat feeding (Soh et al, ).…”

Hyperlipidemia and Allograft Rejection

“…When ApoE −/− mice were fed a high fat diet, significant increases in the basal level of IgG in the serum were noted when compared with either ApoE−/− or wild type mice fed a normal diet, indicating that IgG levels rise in concert with levels of hyperlipidemia, which may be of particular interest in the setting of antibody mediated graft dysfunction. Further study of B cell subsets in hyperlipidemic mice indicate that while at 6 weeks of age, wild type and ApoE deficient mice have similar B cell subset distribution, by 24 weeks of age, the hyperlipidemic mice demonstrate a two fold increase in the total number of marginal zone B cells in comparison with wild type mice (87). Marginal zone B cells have been implicated in the generation of T independent antibody responses to lipoproteins (88) and xenoantigens.…”