| First Author | Taghavie-Moghadam PL | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 10 | Pages | 3453-3465 |
| PubMed ID | 29055004 | Mgi Jnum | J:251269 |
| Mgi Id | MGI:6104343 | Doi | 10.4049/jimmunol.1601429 |
| Citation | Taghavie-Moghadam PL, et al. (2017) STAT4 Regulates the CD8(+) Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr(-/-) Mice. J Immunol 199(10):3453-3465 |
| abstractText | 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 (MPhis) also affected the Tfh/CD8(+) Treg axis, because conditioned media from Stat4(-/-)Ldlr(-/-) MPhis supported CD8(+) Treg differentiation, but not Tfh cell differentiation, in a TGF-beta-dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr(-/-) mice via STAT4-dependent MPhis, as well as cell-intrinsic suppression of CD8(+) Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response. |
