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

Summary 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.