The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4^-/-Ldlr^-/- mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4^-/-Ldlr^-/- mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr^-/- controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8⁺ regulatory T cells (Tregs) in spleens and aortas of Stat4^-/-Ldlr^-/- mice compared with Ldlr^-/- mice. Similarly, STAT4 deficiency supported CD8⁺ Treg differentiation in vitro. STAT4-deficient CD8⁺ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8⁺ Treg functions in vivo. Furthermore, adoptive transfer of Stat4^-/-Ldlr^-/- CD8⁺ Tregs versus Ldlr^-/- CD8⁺ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr^-/- recipients. STAT4 expression in macrophages (MΦs) also affected the Tfh/CD8⁺ Treg axis, because conditioned media from Stat4^-/-Ldlr^-/- MΦs supported CD8⁺ Treg differentiation, but not Tfh cell differentiation, in a TGF-β-dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr^-/- mice via STAT4-dependent MΦs, as well as cell-intrinsic suppression of CD8⁺ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.

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