Taghavie-Moghadam Parésa L, Waseem Tayab C, Hattler Julian, Glenn Lindsey M, Dobrian Anca D, Kaplan Mark H, Yang Yi, Nurieva Roza, Nadler Jerry L, Galkina Elena V
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501.
Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA 23507.
J Immunol. 2017 Nov 15;199(10):3453-3465. doi: 10.4049/jimmunol.1601429. Epub 2017 Oct 20.
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 mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with 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 mice compared with 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 CD8 Tregs versus CD8 Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed recipients. STAT4 expression in macrophages (MΦs) also affected the Tfh/CD8 Treg axis, because conditioned media from 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 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.
代谢综合征和糖尿病状况会促进动脉粥样硬化，但动脉粥样硬化加速的确切机制仍不清楚。尽管最近已确定STAT4在动脉粥样硬化和饮食诱导的胰岛素抵抗（IR）中具有促炎作用，但尚不清楚STAT4在IR条件下对动脉粥样硬化的影响。在本研究中，我们培育了喂食添加胆固醇的致糖尿病饮食（DDC）的小鼠。与对照小鼠相比，喂食DDC的小鼠表现出改善的糖耐量、胰岛素敏感性，动脉粥样硬化减少了36%。有趣的是，与对照小鼠相比，我们在实验小鼠的脾脏和主动脉中检测到T滤泡辅助（Tfh）细胞和血浆B细胞减少，但CD8调节性T细胞（Tregs）急剧升高。同样，STAT4缺陷在体外支持CD8 Treg分化。用钥孔戚血蓝蛋白免疫后，STAT4缺陷的CD8 Tregs抑制Tfh细胞和生发中心B细胞发育，表明STAT4在体内CD8 Treg功能中起重要作用。此外，将实验小鼠的CD8 Tregs与对照小鼠的CD8 Tregs进行过继转移，导致喂食DDC的受体小鼠的斑块负担显著降低，并抑制了Tfh细胞和生发中心B细胞。巨噬细胞（MΦs）中的STAT4表达也影响Tfh/CD8 Treg轴，因为来自实验小鼠MΦs的条件培养基以TGF-β依赖的方式支持CD8 Treg分化，但不支持Tfh细胞分化。这些发现提示了一种新机制，即STAT4通过依赖STAT4的MΦs以及对CD8 Treg生成和功能的细胞内抑制以及Tfh细胞生成和伴随的体液免疫反应的维持，在IR小鼠中支持动脉粥样硬化。
