TY - JOUR
T1 - STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice
AU - Taghavie-Moghadam, Parésa L.
AU - Waseem, Tayab C.
AU - Hattler, Julian
AU - Glenn, Lindsey M.
AU - Dobrian, Anca D.
AU - Kaplan, Mark H.
AU - Yang, Yi
AU - Nurieva, Roza
AU - Nadler, Jerry L.
AU - Galkina, Elena V.
N1 - Funding Information:
This work was supported by Public Health Service, National Heart Lung and Blood Institute Grant HL112605 (to J.L.N., A.D.D., and E.V.G.), HL112605 Supplemental Grant 02S1 (to J.L.N. and P.L.T.-M.), and Grant HL107522 (to E.V.G.) and by National Institute of Allergy and Infectious Diseases Grants AI045515 (to M.H.K.), A1R03AI120027, and 1R21AI20012 (both to R.N.).
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1601429
DO - 10.4049/jimmunol.1601429
M3 - Article
C2 - 29055004
AN - SCOPUS:85033386322
SN - 0022-1767
VL - 199
SP - 3453
EP - 3465
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -