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

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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

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Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Atherosclerosis
Insulin
Insulin Resistance
B-Lymphocytes
Germinal Center
Diet
Adoptive Transfer
Humoral Immunity
Conditioned Culture Medium
Plasma Cells
Aorta
Cell Differentiation
Immunization
Spleen
Macrophages
Cholesterol
Maintenance
Glucose

ASJC Scopus subject areas

  • Immunology

Cite this

STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice. / Taghavie-Moghadam, Parésa L.; Waseem, Tayab C.; Hattler, Julian; Glenn, Lindsey M.; Dobrian, Anca D.; Kaplan, Mark; Yang, Yi; Nurieva, Roza; Nadler, Jerry L.; Galkina, Elena V.

In: Journal of Immunology, Vol. 199, No. 10, 15.11.2017, p. 3453-3465.

Research output: Contribution to journalArticle

Taghavie-Moghadam, PL, Waseem, TC, Hattler, J, Glenn, LM, Dobrian, AD, Kaplan, M, Yang, Y, Nurieva, R, Nadler, JL & Galkina, EV 2017, 'STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice', Journal of Immunology, vol. 199, no. 10, pp. 3453-3465. https://doi.org/10.4049/jimmunol.1601429
Taghavie-Moghadam, Parésa L. ; Waseem, Tayab C. ; Hattler, Julian ; Glenn, Lindsey M. ; Dobrian, Anca D. ; Kaplan, Mark ; Yang, Yi ; Nurieva, Roza ; Nadler, Jerry L. ; Galkina, Elena V. / STAT4 regulates the CD8+ regulatory T Cell/T follicular helper cell axis and promotes atherogenesis in insulin-resistant Ldlr-/- Mice. In: Journal of Immunology. 2017 ; Vol. 199, No. 10. pp. 3453-3465.
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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.",
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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

AU - Yang, Yi

AU - Nurieva, Roza

AU - Nadler, Jerry L.

AU - Galkina, Elena V.

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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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