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

作者：Sun Lishi; Hurez Vincent J; Thibodeaux Suzanne R; Kious Mark J; Liu Aijie; Lin Peiyi; Murthy Kruthi; Pandeswara Srilakshmi; Shin Tahiro; Curiel Tyler J^*

来源：Aging Cell, 2012, 11(3): 509-519.

DOI：10.1111/j.1474-9726.2012.00812.x

• aging
• T cells
• programmed death-1 (PD-1)
• interleukin-17 (IL-17)
• autoimmunity
• regulatory T cells (Tregs)
• STAT3

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 naive 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)-?+ 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 naive 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.

• 出版日期2012-6