RESUMO
Many aspects remain elusive of the mechanisms governing T cell quiescence. Here we show that E protein activity helps to establish a quiescent program in naïve T cells. Decreased E protein activity, as the consequence of enforced expression of an Id1 transgene, led to the accumulation of CD4+CD44hi T cells. The naïve CD4+ T cells from this transgenic strain mounted a vigorous proliferative response upon TCR stimulation, as a result of direct inhibition of E protein activity. Transcriptome analyses demonstrated that Id1-tg naïve CD4+ T cells exhibited a transcriptional profile characteristic of activated CD4+ T cells, with particular enrichment in the gene set related to PI3K-AKT signaling. Western blot analysis confirmed low but constitutive activation of this pathway. Moreover, the Id1-tg CD4+ T cells displayed enhanced formation of TCR microcluster. Taken together, these data support that downregulation of E protein activity facilitates the exit of naïve T cells from quiescence.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Ativação Linfocitária/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Proteína 1 Inibidora de Diferenciação/imunologia , Proteína 1 Inibidora de Diferenciação/metabolismo , Camundongos , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologiaRESUMO
Sjögren's syndrome (SS) is characterized by autoimmune activation and loss of function in the salivary glands. Recent studies reported that bone morphogenetic protein 6 (BMP6), which is a member of transforming growth factor beta (TGF-ß) superfamily, was highly expressed in SS patients. To investigate the role of BMP6 in SS, we treated the salivary gland-derived mesenchymal stem cells (SGMSCs) with BMP6 and found that BMP6 could impair immunomodulatory properties of normal SGMSCs by downregulating the Prostaglandin E2 synthase through DNA-binding protein inhibitor-1. Neutralizing the BMP6 could significantly restore the SGMSC's immunoregulatory function in vitro and delay the SS disease activity in vivo. In conclusion, BMP6 could not only affect the secreting function of epithelial cells in the salivary gland but also influence the immunomodulatory properties of SGMSCs, which may trigger or enhance the autoimmune reflection in SS.
Assuntos
Proteína Morfogenética Óssea 6/farmacologia , Imunomodulação/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Síndrome de Sjogren/genética , Adulto , Animais , Dinoprostona/genética , Dinoprostona/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Feminino , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/imunologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Glândulas Salivares/citologia , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologiaAssuntos
Proteína 1 Inibidora de Diferenciação/genética , Neoplasias/diagnóstico , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/imunologia , Proteína 1 Inibidora de Diferenciação/metabolismo , Técnicas de Diagnóstico Molecular/normas , Neoplasias/genética , Neoplasias/metabolismo , PrognósticoRESUMO
Id proteins are a class of dominant-negative antagonists of helix-loop-helix transcription factors and have been shown to control differentiation of a variety of cell types in diverse organisms. Although the importance of Id1 in tumor endothelial cells is well established, the expression and role of the Id1 protein in human cancer cells is controversial. To explore this issue, we developed and characterized a highly specific rabbit monoclonal antibody against Id1 to assess its expression in human breast, prostate, and bladder malignancies. Our results show that in usual types of human mammary carcinomas, the Id1 protein is expressed exclusively in the endothelium. Interestingly, we detected nuclear expression of the Id1 protein in the tumor cells in 10 of 45 cases of poorly differentiated and highly aggressive carcinoma with metaplastic morphology. Similarly, only 1 of 30 prostate cancer samples showed Id1-positive tumor cells, whereas in almost all, endothelial cells showed high Id1 expression. Intriguingly, whereas normal prostate glands do not show any Id1 protein expression, basal layer cells of benign prostate glands in proximity to tumors expressed high levels of the Id1 protein. In contrast to the lack of Id1 expression in the usual types of mammary and prostate cancers, the majority of transitional cell bladder tumors showed Id1 protein expression in both tumor and endothelial cells. These results suggest that further refinement of Id1 expression patterns in a variety of tumor types will be necessary to identify and study the functional roles played by Id1 in human neoplastic processes.