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Regulación negativa de la activación de las células T y la autoinmunidad por Mgat5 N-glicosilación
M Demetriou1, M Granovsky, S Quaggin
1Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Nature
|February 24, 2001
Resumen
Una deficiencia en la beta1,6 N-acetilglucosaminiltransferasa V (Mgat5) reduce los umbrales de activación de las células T al mejorar el agrupamiento de los receptores de células T (TCR). Esta es la enzima Mgat5.
Área de la Ciencia:
- Inmunología y glucobiología.
- La señalización celular y la activación de células T.
Sus antecedentes:
- La activación de las células T requiere agrupamiento de los receptores de células T (TCR) en los sitios de presentación de antígenos.
- La unión al co-receptor CD28 influye en el agrupamiento de TCR mediante el reclutamiento de proteínas de señalización.
Objetivo del estudio:
- Para investigar el papel de la beta1,6 N-acetilglucosaminiltransferasa V (Mgat5) en los umbrales de activación de las células T.
- Determinar si la deficiencia de Mgat5 afecta el agrupamiento de TCR y las respuestas inmunitarias posteriores.
Principales métodos:
- Análisis de ratones con deficiencia de Mgat5 (Mgat5-/-) y células T.
- Evaluación del reclutamiento de TCR, señalización, reorganización de actin y proliferación.
- Investigación de la interacción de la galectina-3 con el complejo TCR.
- Experimentos in vitro con lactosa para inhibir la unión de la galectina.
Principales resultados:
- La deficiencia de Mgat5 mejoraba el reclutamiento de TCR, la señalización, la reorganización de la actina y la proliferación en las células T.
- Los ratones Mgat5-/- exhibieron enfermedad renal autoinmune, hipersensibilidad de tipo retrasado aumentada y mayor susceptibilidad a la encefalomielitis autoinmune experimental.
- Mgat5 facilita la ramificación de GlcNAc beta1,6, aumentando los ligandos de N-acetilactosamina para las galectinas, incluida la galectina-3, que se asocia con el complejo TCR.
- El pretratamiento con lactosa imitaba la agrupación de células Mgat5-/- T, lo que sugiere un papel para las interacciones galectina-glicano.
Conclusiones:
- La glicosilación mediada por Mgat5 fortalece una red de galectina-glicoproteína que restringe el reclutamiento de TCR.
- La desregulación de Mgat5 puede predisponer a las personas a enfermedades autoinmunes como la esclerosis múltiple.
- Dirigirse a las vías dependientes de Mgat5 podría ofrecer estrategias terapéuticas para enfermedades autoinmunes.
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