RESUMEN
The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr(-/-) mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr(-/-) mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr(-/-) mice. Mechanistically, the heightened inflammation in Pxr(-/-) mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.
Asunto(s)
Listeria monocytogenes/patogenicidad , Listeriosis/inmunología , Receptores de Esteroides/genética , Receptor Toll-Like 4/metabolismo , Animales , Técnicas de Inactivación de Genes , Inmunidad Innata , Listeriosis/metabolismo , Listeriosis/microbiología , Ratones , Monocitos/metabolismo , Receptor X de Pregnano , Receptores de Esteroides/metabolismo , Transducción de Señal , Receptor Toll-Like 2/metabolismoRESUMEN
The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.
Asunto(s)
Activación de Linfocitos/inmunología , Células T Asesinas Naturales/inmunología , Mucosa Respiratoria/inmunología , Tularemia/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Francisella tularensis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía ConfocalRESUMEN
NK cells are the main cells of the innate immune system that produce IFN-γ, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of IFN-γ-competence in CD4(+) T helper cells requires a differentiation process from naïve toward type 1 (Th1) cells, which is associated with epigenetic remodeling at the IFNG locus. In the present study, we show that the ability of NK cells to produce IFN-γ in response to activating receptor (actR) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher NF-κB activation in response to actR triggering. Moreover, during the differentiation process NK cells gradually display increasing expression of IFNG and TBX21 (encoding T-bet) transcripts and demethylation at the IFNG promoter. This study provides new insights in the molecular mechanisms underlying NK-cell ability to express IFN-γ upon actR engagement. Thus, we propose that in order to efficiently produce IFN-γ in response to infected or transformed cells, NK cells gain Th1-like features, such as higher IFN-γ competence and epigenetic remodeling of the IFNG promoter, during their terminal differentiation.
Asunto(s)
Diferenciación Celular , Interferón gamma/biosíntesis , Células Asesinas Naturales/inmunología , Islas de CpG , Metilación de ADN , Humanos , Interferón gamma/genética , Células Asesinas Naturales/citología , FN-kappa B/fisiología , Subfamilia K de Receptores Similares a Lectina de Células NK/fisiología , Receptor 1 Gatillante de la Citotoxidad Natural/fisiología , Receptor 3 Gatillante de la Citotoxidad Natural/fisiología , Regiones Promotoras Genéticas , Proteínas de Dominio T Box/fisiologíaRESUMEN
Many studies have examined pathways controlling effector T cell differentiation, but less is known about the fate of individual CD8+ T cells during infection. Here, we examine the antiviral and antibacterial responses of single CD8+ T cells from the polyclonal repertoire. The progeny of naive clonal CD8+ T cells displayed unique profiles of differentiation based on extrinsic pathogen-induced environmental cues, with some clones demonstrating extreme bias toward a single developmental pathway. Moreover, even within the same animal, a single naive CD8+ T cell exhibited distinct fates that were controlled by tissue-specific events. However, memory CD8+ T cells relied on intrinsic factors to control differentiation upon challenge. Our results demonstrate that stochastic and instructive events differentially contribute to shaping the primary and secondary CD8+ T cell response and provide insight into the underlying forces that drive effector differentiation and protective memory formation.