RESUMO
Interactions between the microbiota and mammalian host are essential for defense against infection, but the microbial-derived cues that mediate this relationship remain unclear. Here, we find that intestinal epithelial cell (IEC)-associated commensal bacteria, segmented filamentous bacteria (SFB), promote early protection against the pathogen Citrobacter rodentium, independent of CD4+ T cells. SFB induced histone modifications in IECs at sites enriched for retinoic acid receptor motifs, suggesting that SFB may enhance defense through retinoic acid (RA). Consistent with this, inhibiting RA signaling suppressed SFB-induced protection. Intestinal RA levels were elevated in SFB mice, despite the inhibition of mammalian RA production, indicating that SFB directly modulate RA. Interestingly, RA was produced by intestinal bacteria, and the loss of bacterial-intrinsic aldehyde dehydrogenase activity decreased the RA levels and increased infection. These data reveal RA as an unexpected microbiota-derived metabolite that primes innate defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat infections.
Assuntos
Bactérias/metabolismo , Enteropatias/metabolismo , Simbiose , Tretinoína/metabolismo , Animais , Bacillus cereus , Bifidobacterium bifidum , Linfócitos T CD4-Positivos , Citrobacter rodentium , Células Epiteliais , Código das Histonas , Interações entre Hospedeiro e Microrganismos , Enteropatias/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , Óxido Nítrico , Transdução de SinaisAssuntos
Proteínas Alimentares/efeitos adversos , Inflamação/veterinária , Proteínas de Soja/efeitos adversos , Doenças dos Suínos/etiologia , Animais , Biomarcadores , Biópsia , Proteínas Alimentares/imunologia , Enterocolite/diagnóstico , Enterocolite/etiologia , Proteínas de Soja/imunologia , Suínos , Doenças dos Suínos/diagnósticoRESUMO
Langerhans cells (LC) are the prototype langerin-expressing dendritic cells (DC) that reside specifically in the epidermis, but langerin-expressing conventional DCs also reside in the dermis and other tissues, yet the factors that regulate their development are unclear. Because retinoic acid receptor alpha (RARα) is highly expressed by LCs, we investigate the functions of RARα and retinoic acid (RA) in regulating the langerin-expressing DCs. Here we show that the development of LCs from embryonic and bone marrow-derived progenitors and langerin+ conventional DCs is profoundly regulated by the RARα-RA axis. During LC differentiation, RARα is required for the expression of a LC-promoting transcription factor Runx3, but suppresses that of LC-inhibiting C/EBPß. RARα promotes the development of LCs and langerin+ conventional DCs only in hypo-RA conditions, a function effectively suppressed at systemic RA levels. Our findings identify positive and negative regulatory mechanisms to tightly regulate the development of the specialized DC populations.
Assuntos
Antígenos de Superfície/metabolismo , Células Dendríticas/metabolismo , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Animais , Antígenos de Superfície/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Perfilação da Expressão Gênica , Humanos , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor alfa de Ácido Retinoico/genéticaRESUMO
The ability of follicular T cells to migrate into B-cell follicles is central for them to participate in germinal center responses. The chemokine receptor CXCR5 is expressed by both Tfh and Tfr cells and is the defining marker for follicular T cells. In addition, Tfh and Tfr cells express additional chemokine receptors to enable them to interact with B cells and other cell types. CXCR5(+) Tfh and Tfr cells are divided into CCR7(+) perifollicular cells and CCR7(-) follicular cells. Most of the CXCR5(+) CCR7(-) Tfh cells reside in germinal centers and are called GC T cells. The methods to identify human Tfh and Tfr cell subsets based on chemokine receptors and other antigens and assess their migration potential are provided in this article.