Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells

Lishi Sun, Vincent J. Hurez, Suzanne R. Thibodeaux, Mark J. Kious, Aijie Liu, Peiyi Lin, Kruthi Murthy, Srilakshmi Pandeswara, Tahiro Shin, Tyler J. Curiel

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38 Scopus citations

Abstract

Regulatory T cells (Tregs) are specialized CD4+ T lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation and autoimmunity, few reports address age effects of immune regulation or auto-aggressive T cells. We show here that young and aged naïve CD4+ T cells are equivalently auto-aggressive in vivo in T cell-driven autoimmune colitis. Young and aged CD4+ Tregs equally suppressed age-matched T cell proliferation in vitro and controlled clinical and pathologic T cell-driven autoimmune colitis, suggesting equivalent regulatory function. However, whereas young and aged CD4+ Tregs suppressed interferon (IFN)-γ+ T cells equivalently in this model, aged CD4+ Tregs unexpectedly failed to restrain interleukin (IL)-17+ T cells. Nonetheless, young and aged CD4+ Tregs equally restrained IL-17+ T cells in vivo during acute inflammation, suggesting a chronic inflammation-related defect in aged CD4+ Tregs. In support, aged Tregs expressed reduced STAT3 activation, a defect associated with poor IL-17-producing T cell restraint. Aged naïve mice had markedly increased programmed death (PD)-1+ T cells, but these exhibited no significant auto-aggressive or regulatory functions in T cell-driven colitis. Young CD8+CD122- T cells induce autoimmune bone marrow failure, but we show that aged CD8+CD122- T cells do not. These data demonstrate no apparent age-related increase in auto-aggressive T cell behavior, but disclose previously unrecognized functional defects in aged CD4+ Tregs during chronic inflammation. IL-17 can be inflammatory and contributes to certain autoimmune disorders. Reduced aged Treg function during chronic inflammation and reduced IL-17 restraint could contribute to age-related inflammation or autoimmunity.

Original languageEnglish (US)
Pages (from-to)509-519
Number of pages11
JournalAging cell
Volume11
Issue number3
DOIs
Publication statusPublished - Jun 1 2012

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Keywords

  • Aging
  • Autoimmunity
  • Interleukin-17 (IL-17)
  • Programmed death-1 (PD-1)
  • Regulatory T cells (Tregs)
  • STAT3
  • T cells

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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