STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis

Cheng-Rong Yu, Ivy M Dambuza, Yong-Jun Lee, Gregory M Frank, Charles E Egwuagu

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3 Downloads (Pure)

Abstract

STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD). The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A), p21(waf1), p27(KIP1), Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1) infection and experimental autoimmune uveitis (EAU). Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg) implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.

Original languageEnglish
Article number359674
JournalMediators of Inflammation
Volume2013
DOIs
Publication statusPublished - 2013

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Uveitis
Human Herpesvirus 1
Regulatory T-Lymphocytes
Interleukin-10
T-Lymphocytes
Infection
Cell Death
Viruses
Forkhead Transcription Factors
Encephalomyelitis
Interleukin-17
Interleukin-2
Cell Differentiation
Interleukin-6
Cell Survival
Up-Regulation
Down-Regulation
Inflammation
Phenotype
Therapeutics

Keywords

  • Animals
  • Apoptosis
  • Autoimmune Diseases/immunology
  • CD8-Positive T-Lymphocytes/cytology
  • Cell Proliferation
  • Cell Separation
  • Flow Cytometry
  • Gene Expression Regulation
  • Herpes Simplex/metabolism
  • Herpesvirus 1, Human
  • Inflammation
  • Interleukin-10/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • STAT3 Transcription Factor/genetics
  • Up-Regulation
  • Uveitis/immunology

Cite this

STAT3 regulates proliferation and survival of CD8+ T cells : enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. / Yu, Cheng-Rong; Dambuza, Ivy M; Lee, Yong-Jun; Frank, Gregory M; Egwuagu, Charles E.

In: Mediators of Inflammation, Vol. 2013, 359674, 2013.

Research output: Contribution to journalArticle

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abstract = "STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD). The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A), p21(waf1), p27(KIP1), Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1) infection and experimental autoimmune uveitis (EAU). Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg) implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.",
keywords = "Animals, Apoptosis, Autoimmune Diseases/immunology, CD8-Positive T-Lymphocytes/cytology, Cell Proliferation, Cell Separation, Flow Cytometry, Gene Expression Regulation, Herpes Simplex/metabolism, Herpesvirus 1, Human, Inflammation, Interleukin-10/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, STAT3 Transcription Factor/genetics, Up-Regulation, Uveitis/immunology",
author = "Cheng-Rong Yu and Dambuza, {Ivy M} and Yong-Jun Lee and Frank, {Gregory M} and Egwuagu, {Charles E}",
year = "2013",
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journal = "Mediators of Inflammation",
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T2 - enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis

AU - Yu, Cheng-Rong

AU - Dambuza, Ivy M

AU - Lee, Yong-Jun

AU - Frank, Gregory M

AU - Egwuagu, Charles E

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AB - STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD). The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A), p21(waf1), p27(KIP1), Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1) infection and experimental autoimmune uveitis (EAU). Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg) implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.

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KW - Apoptosis

KW - Autoimmune Diseases/immunology

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KW - Cell Separation

KW - Flow Cytometry

KW - Gene Expression Regulation

KW - Herpes Simplex/metabolism

KW - Herpesvirus 1, Human

KW - Inflammation

KW - Interleukin-10/metabolism

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Phenotype

KW - STAT3 Transcription Factor/genetics

KW - Up-Regulation

KW - Uveitis/immunology

U2 - 10.1155/2013/359674

DO - 10.1155/2013/359674

M3 - Article

C2 - 24204098

VL - 2013

JO - Mediators of Inflammation

JF - Mediators of Inflammation

SN - 0962-9351

M1 - 359674

ER -