IL-15 Improves Aging-Induced Persistent T Cell Exhaustion in Mouse Models of Repeated Sepsis

Aging is a grave problem in sepsis, and T cell exhaustion is the main cause of sepsis-induced immunosuppression. Sepsis- and aging-induced T cell exhaustion is related to secondary infection with a poor long-term outcome in the elderly. However, the trend, impact, and mechanism of T cell exhaustion are still unclear. Interleukin (IL)-15 improves survival rate of septic mice via its antiapoptotic effect on T cells; however, it is still unclear how IL-15 reverses prolonged T cell exhaustion in aged septic mice. The purpose of this study was to clarify the trend of sepsis-induced T cell exhaustion and whether IL-15 prevents aging-induced persistent T cell exhaustion in septic mice. Preserved cecal slurry was injected intraperitoneally into young (6-week-old) and aged mice (18-24-month-old) 4 times, to induce clinically relevant repeated sepsis. IL-15 (1.5 μg) or phosphate-buffered saline was injected subcutaneously 3 times, body weight was serially measured, and peripheral blood cells from their cheek were serially collected for 50 days. Sepsis-induced T cell exhaustion was significantly severe in aged mice than in young mice and was accompanied with decreased naive CD4 and CD8 T cells (P < 0.01) and increased expression of program death 1 on T cell (P < 0.01) and regulatory T cell population (P < 0.01). IL-15 significantly improved sepsis-induced T exhaustion, with significantly increased numbers of natural killer cells and macrophages, and significantly enhanced phagocytosis activity in aged septic mice (P < 0.05). It decreased the long-term mortality associated with sepsis survivors by improving T cell exhaustion over an extended duration and also ameliorated aging-induced persistent T cell exhaustion in septic mice.