IL-15 synergizes with IL-12 to enhance NK cell function in vivo during chronic SIV infection

Abstract

Abstract Natural killer (NK) cells play a critical role in viral immunity. During early HIV/SIV infection, they are known to protect/limit viremia at the very early stage of infection. However, during chronic HIV infection NK cells are less functional, thus elicitation of highly functional NK cells are important for HIV cure strategy. It has been shown that cytokines IL-15 and IL-12 individually can activate NK cells during SIV infection. However, the synergistic effect of these cytokines to induce NK cell function has not been studied. We performed in vivo experiment to evaluate the effect of cytokines IL-15 (20ug/Kg)/IL-15R(100ug/kg) and IL-12 (10ug/kg) and its combination in inducing functional NK cells during chronic infection (6 weeks PI) and with no cytokine treatment as a control. Lymphocytes from blood and lymph nodes were analyzed for NK cell functions using multicolor flow cytometry. Our in vivo data clearly indicates that IL-15/IL-15R synergistically act with IL-12 to induce proliferation (Ki-67) and cytotoxicity (Granzyme-B+) of NK cells both in blood and lymph node. Interestingly, the cytotoxic NK cells CD16+ (FCgRIII) expanded significantly in the combination group. In addition, the degranulation capacity of NK cells (IFN-gamma+ CD107a+) significantly enhanced in the combination group when compared to either cytokine group alone, suggesting that combined cytokine treatment enhanced NK cell cytotoxicity during chronic SIV infection. Our data clearly showed that the combination of IL-15 plus IL-12 cytokine treatment increased NK cell function in vivo with proliferative and cytotoxic capacity, which is important for HIV cure strategy considering directing functional NK cells to immune privileged sites such as lymph nodes. This work was supported in part by National Institutes of Health Grants CFAR R03, R01 HD095741-01, 1R01AI148377-01A1 (to VV), U19 AI109633 (to R.R.A.), Emory University CFAR grant P30 AI050409, NIH Office of Research Infrastructure Programs (ORIP) grants P51 OD011132 and U42 OD011023 (to YNPRC) and R24 OD010947 to the Resource for NHP Immune Reagents.