RESUMO
We report a novel KRT13 germ line variant that causes white sponge nevus (WSN) with mucosal dysplasia. Genital, vaginal, and cervical WSN were observed in four female patients, of whom two had premalignant cervical lesions at young age. Two of the 12 patients with oral WSN developed oral squamous cell carcinoma.
RESUMO
Dendritic cell (DC) maturation results in changes in antigen processing and presentation, governing the fate of adaptive immunity. Understanding the intracellular signaling pathways governing DC maturation is therefore critical. In this study, we observed that the kinase, GSK-3ß, is present in its active form in resting immature DCs isolated from the spleen and bone marrow of mice. Induction of DC maturation using GM-CSF, IL-4 and TNF-α resulted in GSK-3ß inhibition, as reflected by increased phosphorylation of Serine 9 on the kinase, and concomitant stabilization of its substrate, ß-catenin. Treatment of immature DCs with a GSK-3ß inhibitor increased cell surface expression of CD80, CD86 and CD40 on DCs, enhancing their ability to present antigen and activating IL-2 secretion by T cells. GSK-3ß inhibition also parallels dendritic cell maturation in vivo. Our results show that GSK-3ß signaling controls DC maturation and suggest that this kinase could be manipulated to modulate adaptive immunity.
Assuntos
Células Dendríticas/citologia , Células Dendríticas/enzimologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Imunidade Adaptativa , Animais , Apresentação de Antígeno/efeitos dos fármacos , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Diferenciação Celular/fisiologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Interleucina-2/biossíntese , Interleucina-4/farmacologia , Masculino , Maleimidas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Fagocitose/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Recombinantes , Serina/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia , Especificidade por Substrato , Fator de Necrose Tumoral alfa/farmacologia , beta Catenina/metabolismoRESUMO
The mechanism by which regulatory T (Treg) cells suppress the immune response is not well defined. A recent study has shown that ß-catenin prolongs Treg cell survival. Because ß-catenin is regulated by glycogen synthase kinase 3ß (GSK-3ß)-directed phosphorylation, we focused on GSK-3ß and the role it plays in Treg cell function. Inhibition of GSK-3ß led to increased suppression activity by Treg cells. Inhibitor-treated Treg cells exhibited prolonged FoxP3 expression and increased levels of ß-catenin and of the antiapoptotic protein Bcl-xL. Systemic administration of GSK-3ß inhibitor resulted in prolonged islet survival in an allotransplant mouse model. Our data suggest that GSK-3ß could be a useful target in developing strategies designed to increase the stability and function of Treg cells for inducing allotransplant tolerance or treating autoimmune conditions.
