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

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.