RESUMEN
IL-21 is a Type I cytokine, which uses the common gamma chain (gamma(c)) in its receptor. As members of the gamma(c) cytokine/cytokine receptors family play crucial role in the differentiation, activation, and survival of lymphocytes, we have investigated if IL-21 could promote T cell survival and thus, contribute to T cell homeostasis and expansion. Unlike most gamma(c) cytokine receptors, we report that IL-21R is constitutively expressed by all mature T lymphocytes and that stromal cells of lymphoid organs are a constitutive source of IL-21. These observations are reminiscent of what is observed for IL-7/IL-7R, which control T cell survival and homeostasis and suggest a role for IL-21 in T cell homeostasis. Indeed, our results show that IL-21 is a survival factor for resting and activated T cells. Moreover, the ability of IL-21 to costimulate T cell proliferation is mediated by enhancing T cell viability. Further investigation of how IL-21R signaling induces T cell survival shows for the first time that IL-21 binding to its receptor activates the PI-3K signaling pathway and induces Bcl-2 expression. Moreover, the activation of the PI-3K signaling pathway is essential for IL-21-mediated T cell survival. Our data provide a new role for IL-21 in the immune system, which might be used to improve T cell homeostasis in immunocompromised patients.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Interleucinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T/citología , Animales , Western Blotting , Tamaño de la Célula , Activación Enzimática , Citometría de Flujo , Subunidad alfa del Receptor de Interleucina-21/genética , Subunidad alfa del Receptor de Interleucina-21/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Linfocitos T/metabolismoRESUMEN
The ability of IL-21 to promote in vitro T cell survival led us to investigate its biological activity in vivo. We report that overexpression of IL-21 in transgenic mice drives CD8(+) memory T cell accumulation with a concomitant reduction in naive T cell numbers. These memory T cells are functional, given their ability to rapidly produce IFN-gamma and proliferate following stimulation. Since the homeostasis of naive and memory T cells is controlled by cytokines, we evaluated whether IL-21 influences cytokine receptor expression. We show that IL-21 inhibits IL-7R expression on naive T cells in vitro, suggesting impaired IL-7-mediated naive T cell survival in IL-21-transgenic mice. In contrast, IL-7R expression on CD4(+) memory T cells is not affected, allowing their IL-7-dependent survival in IL-21-transgenic mice. Although IL-21 decreases IL-7R expression on CD8(+) memory T cells, this has no impact on their survival since their maintenance in the T cell pool is IL-7-independent. Rather, we demonstrate that CD8(+) memory T cells are receptive to IL-21 survival signals allowing for their accumulation in IL-21-transgenic mice. This study identifies new roles for IL-21 in T cell homeostasis and in the regulation of T cell responses to cytokines.