STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice

Parésa L. Taghavie-Moghadam, Tayab C. Waseem, Julian Hattler, Lindsey M. Glenn, Anca D. Dobrian, Mark Kaplan, Yi Yang, Roza Nurieva, Jerry L. Nadler, Elena V. Galkina

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 (MFs) also affected the Tfh/CD8+ Treg axis, because conditioned media from Stat4-/-Ldlr-/- MFs 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 MFs, as well as cell-intrinsic suppression of CD8+ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.

Original languageEnglish (US)
Pages (from-to)3453-3465
Number of pages13
JournalJournal of Immunology
Volume199
Issue number10
DOIs
StatePublished - Nov 15 2017

    Fingerprint

ASJC Scopus subject areas

  • Immunology

Cite this

Taghavie-Moghadam, P. L., Waseem, T. C., Hattler, J., Glenn, L. M., Dobrian, A. D., Kaplan, M., Yang, Y., Nurieva, R., Nadler, J. L., & Galkina, E. V. (2017). STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice. Journal of Immunology, 199(10), 3453-3465. https://doi.org/10.4049/jimmunol.1601429