IL-21 augments natural killer effector functions in chronically HIV-infected individuals

Objective:: This study addresses the interleukin (IL)-21 effects on resting peripheral blood natural killer (NK) cells in chronically HIV-infected individuals. Design:: The effects of IL-21 on perforin expression, proliferation, degranulation, interferon (IFN)-γ production, cytotoxicity and induction of STAT phosphorylation in NK cells were determined in vitro. Methods:: Peripheral blood mononuclear cells from HIV-infected and healthy individuals were incubated in vitro for 6 h, 24 h or 5 days with IL-21 or IL-15. Percentages of perforin, IFN-γ, CD107a, NKG2D and STAT3ĝ€ "5 positive cells were determined within NK cell populations. K562 cells were used as target cells in NK cytotoxicity assay. Results:: Frequency of CD56 cells in chronically HIV-infected individuals was diminished. Perforin expression in CD56 and CD56 was comparable in healthy and HIV-infected individuals. IL-15 upregulated perforin expression primarily in CD56 NK cells, whereas IL-21 upregulated perforin in both NK subsets. IL-21 and IL-15 upregulated CD107a and IFN-γ, as well as NK cytotoxicity. IL-15 predominantly activated STAT5, whereas IL-21 activated STAT5 and STAT3. IL-15, but not IL-21 increased NK cell proliferation in uninfected and HIV-infected individuals. Conclusion:: IL-21 augments NK effector functions in chronically HIV-infected individuals and due to its perforin enhancing properties it has potential for immunotherapy or as a vaccine adjuvant.