RESUMEN
IL-27 is a cytokine that regulates Th function during autoimmune and pathogen-induced immune responses. Although previous studies have shown that regulatory T cells (Tregs) express the IL-27R, and that IL-27 inhibits forkhead box P3 upregulation in vitro, little is known about how IL-27 influences Tregs in vivo. The studies presented in this article show that mice that overexpress IL-27 had decreased Treg frequencies and developed spontaneous inflammation. Although IL-27 did not cause mature Tregs to downregulate forkhead box P3, transgenic overexpression in vivo limited the size of a differentiating Treg population in a bone marrow chimera model, which correlated with reduced production of IL-2, a vital cytokine for Treg maintenance. These data identify an indirect role for IL-27 in shaping the Treg pool.
Asunto(s)
Diferenciación Celular/inmunología , Inhibidores de Crecimiento/fisiología , Interleucinas/fisiología , Subunidades de Proteína/fisiología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Diferenciación Celular/genética , Células Cultivadas , Femenino , Inhibidores de Crecimiento/biosíntesis , Inhibidores de Crecimiento/genética , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-2/antagonistas & inhibidores , Interleucina-2/biosíntesis , Interleucinas/biosíntesis , Interleucinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Antígenos de Histocompatibilidad Menor , Subunidades de Proteína/biosíntesis , Subunidades de Proteína/genética , Quimera por Radiación/inmunología , Receptores de Citocinas/biosíntesis , Receptores de Citocinas/genética , Receptores de Citocinas/fisiología , Linfocitos T Reguladores/patologíaRESUMEN
The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit of its receptor, combined with gp130, a common receptor chain used by several cytokines, including IL-6. Notably, the IL-27 subunits p28 (IL-27p28) and EBI3 are not always expressed together, which suggests that they may have unique functions. Here we show that IL-27p28, independently of EBI3, antagonized cytokine signaling through gp130 and IL-6-mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. Mice transgenic for expression of IL-27p28 showed a substantial defect in the formation of germinal centers and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.
Asunto(s)
Receptor gp130 de Citocinas/metabolismo , Interleucinas/metabolismo , Transducción de Señal/inmunología , Animales , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Separación Celular , Receptor gp130 de Citocinas/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunohistoquímica , Interleucinas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Antígenos de Histocompatibilidad Menor , Receptores de Citocinas/inmunología , Receptores de Citocinas/metabolismoRESUMEN
Previous studies have implicated T cell production of IL-17 in resistance to Toxoplasma gondii as well as the development of immune-mediated pathology during this infection. Analysis of C57BL/6 and C57BL/6 RAG(-/-) mice challenged with T. gondii-identified NK cells as a major innate source of IL-17. The ability of soluble Toxoplasma Ag to stimulate NK cells to produce IL-17 was dependent on the presence of accessory cells and the production of IL-6, IL-23, and TGF-beta. In contrast, these events were inhibited by IL-2, IL-15, and IL-27. Given that IL-6 was one of the most potent enhancers of NK cell production of IL-17, further studies revealed that only a subset of NK cells expressed both chains of the IL-6R, IL-6 upregulated expression of the Th17-associated transcription factor RORgammat, and that IL-6(-/-) mice challenged with T. gondii had a major defect in NK cell production of IL-17. Together, these data indicate that many of the same cytokines that regulate Th17 cells are part of a conserved pathway that also control innate production of IL-17 and identify a major role for IL-6 in the regulation of NK cell responses.