RESUMEN
A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.
Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Pulmón/inmunología , Pulmón/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Células Th2/inmunología , Animales , Asma/complicaciones , Diferenciación Celular , Factor de Transcripción GATA3/metabolismo , Inmunoglobulina E/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Interleucinas/metabolismo , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Pyroglyphidae/inmunología , Receptores de Interleucina-21/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Together, Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. These data elucidate the signals required for Blimp-1 expression in TH2 cells and reveal an unexpected mechanism of action of IL-10 in T cells, providing insights into the molecular underpinning by which Blimp-1 constrains T cell expansion to limit autoimmunity.