Interleukin-21 up-regulates interleukin-21R expression and interferon gamma production by CD8+ cells in SHIV-infected macaques

Interleukin-21 (IL-21) is produced primarily by CD4+T cells and regulates immunity against human/simian immunodeficiency virus (HIV/SIV) infection. Activated CD8+ cells and their secreted interferon-gamma (IFN-gamma) are crucial for the control of acute HIV/SIV infection. However, whether IL-21 can regulate IFN-gamma production by CD8+ cells remains controversial. Rhesus macaques (RMs, n = 8) were infected with SHIV and the levels of plasma IL-21, IFN-gamma and the frequency of peripheral blood activated T cells were measured longitudinally. Following infection with SHIV, the levels of plasma IL-21 and IFN-gamma increased, peaked at 17 days postinfection and declined later. Furthermore, IL-21 induced IL-21 receptor (IL-21R) and IFN-gamma, perforin, but not granmyze B, expression in CD8+ cells from four selected SHIV-infected RMs. The regulatory effect of IL-21 on CD8+ cell function appeared to be associated with increased levels of STAT3, but not STAT5, phosphorylation in CD8+ cells from SHIV-infected RMs. In parallel, treatment with soluble IL-21R/Fc, an inhibitor of IL-21-induced activation of JAK1/3 and STAT3, abrogated IL-21-induced STAT3 activation and IFN-gamma production in CD8+ cells from SHIV-infected RMs in vitro. Our data indicated that IL-21 was a positive regulator of IFN-gamma secreting CD8+ cells and increased the STAT3 phosphorylation, regulating T-cell immunity against acute SHIV infection in RMs. Our findings may provide a new basis for the development of immunotherapies for the control of SHIV/HIV infection.