RESUMO
Accumulation of T follicular helper (Tfh) cells and proinflammatory cytokines drive autoantibody-mediated diseases. The RNA-binding protein Roquin-1 (Rc3h1) represses the inducible costimulator ICOS and interferon-γ (IFN-γ) in T cells to prevent Tfh cell accumulation. Unlike Rc3h1(san) mice with a mutation in the ROQ domain of Roquin-1, mice lacking the protein, paradoxically do not display increased Tfh cells. Here we have analyzed mice with mutations that eliminate the RING domain from Roquin-1 or its paralog, Roquin-2 (Rc3h2). RING or ROQ mutations both disrupted Icos mRNA regulation by Roquin-1, but, unlike the ROQ mutant that still occupied mRNA-regulating stress granules, RING-deficient Roquin-1 failed to localize to stress granules and allowed Roquin-2 to compensate in the repression of ICOS and Tfh cells. These paralogs also targeted tumor necrosis factor (TNF) in nonlymphoid cells, ameliorating autoantibody-induced arthritis. The Roquin family emerges as a posttranscriptional brake in the adaptive and innate phases of antibody responses.
Assuntos
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Necrose Tumoral alfa/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Imunidade Adaptativa/genética , Animais , Formação de Anticorpos/genética , Linhagem Celular , Imunidade Inata/genética , Camundongos , Camundongos Mutantes , Mutação/genética , Domínios RING Finger/genética , Proteínas Repressoras/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Lipid antigens trigger help from natural killer T cells (NKT cells) for B cells, and direct conjugation of lipid agonists to antigen profoundly augments antibody responses. Here we show that in vivo, NKT cells engaged in stable and prolonged cognate interactions with B cells and induced the formation of early germinal centers. Mouse and human NKT cells formed CXCR5(+)PD-1(hi) follicular helper NKT cells (NKT(FH) cells), and this process required expression of the transcriptional repressor Bcl-6, signaling via the coreceptor CD28 and interaction with B cells. NKT(FH) cells provided direct cognate help to antigen-specific B cells that was dependent on interleukin 21 (IL-21). Unlike T cell-dependent germinal centers, those driven by NKT(FH) cells did not generate long-lived plasma cells. Our results demonstrate the existence of a Bcl-6-dependent subset of NKT cells specialized in providing help to B cells.
Assuntos
Linfócitos B/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Comunicação Celular/imunologia , Células Cultivadas , Centro Germinativo/imunologia , Humanos , Imunofenotipagem , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , FenótipoRESUMO
Recently, it has been shown that female rats receiving very large doses (e.g., 2 mg) of estradiol valerate (EV) take considerably more alcoholic beverage than placebo controls. The question asked, with these procedures, is whether the enhanced appetite for alcoholic beverages was specific to those beverages or was a reflection of a general increase in appetite. Female rats were provided with various sweetened beverages. In one experiment, they were provided a palatable saccharin solution (0.25% solution) and a less palatable one (2% saccharin solution). EV treatment led to more intake of the palatable saccharin solution and reduced intake of the less palatable solution. EV induces changes leading to enhanced appetite for some ingesta (including palatable saccharin solutions and alcoholic beverages), but surely not all ingesta.