title: Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells.
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.
authors.affiliation: Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Lishi
authors.initials: L
authors.lastname: Sun
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hurez
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Thibodeaux
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kious
authors.forename: Aijie
authors.initials: A
authors.lastname: Liu
authors.forename: Peiyi
authors.initials: P
authors.lastname: Lin
authors.forename: Kruthi
authors.initials: K
authors.lastname: Murthy
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Pandeswara
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000367:Age Factors; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat