RESUMEN
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-γ) are crucial for the control of acute HIV/SIV infection. However, whether IL-21 can regulate IFN-γ production by CD8+ cells remains controversial. Rhesus macaques (RMs, n = 8) were infected with SHIV and the levels of plasma IL-21, IFN-γ and the frequency of peripheral blood activated T cells were measured longitudinally. Following infection with SHIV, the levels of plasma IL-21 and IFN-γ increased, peaked at 17 days postinfection and declined later. Furthermore, IL-21 induced IL-21 receptor (IL-21R) and IFN-γ, 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-γ production in CD8+ cells from SHIV-infected RMs in vitro. Our data indicated that IL-21 was a positive regulator of IFN-γ-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.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , VIH , Interferón gamma/metabolismo , Interleucinas/farmacología , Enfermedades de los Monos/virología , Receptores de Interleucina-21/metabolismo , Virus de la Inmunodeficiencia de los Simios , Regulación hacia Arriba/efectos de los fármacos , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Infecciones por VIH/veterinaria , Técnicas In Vitro , Macaca mulatta , Masculino , Enfermedades de los Monos/metabolismo , Enfermedades de los Monos/patología , Perforina/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Recombinantes/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patologíaRESUMEN
The cytokine interleukin-21 (IL-21) regulates viral pathogenesis in individuals infected with human and simian immunodeficiency viruses. However, because the time of initial infection with HIV in humans is rarely known, the dynamics of IL-21 production during the first weeks have not been adequately explored. In the present study, we used rhesus macaques to model the first stages of infection. Twenty-two rhesus macaques were infected rectally with simian-human immunodeficiency virus (SHIV)-1157ipd3N4, and for 12 weeks, replication of the virus, the numbers of CD4+ and CD8+ T cells, and the levels of plasma IL-21 were monitored. Our study demonstrated that plasma levels of IL-21 increased during the early phase of SHIV infection when compared with the values observed before inoculation. We conclude that IL-21 has a likely role in the immunopathogenesis of HIV/SIV/SHIV.