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Determining Optimal Cytotoxic Activity of Human Her2neu Specific CD8 T cells by Comparing the Cr51 Release Assay to the xCELLigence System
Published on: August 8, 2012
Inactivación de las células T CD8 mal seleccionadas por metilación del gen CD8 y muerte celular
G A Pestano1, Y Zhou, L A Trimble
1Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston MA 02115, USA.
Science (New York, N.Y.)
|May 15, 1999
Resumen
Las células CD8 seleccionadas erróneamente son purgadas por un mecanismo de control de calidad posttimo. La falta de activación de los receptores de células T (TCR) y los coreceptores CD8 desencadena la apoptosis, lo que previene las enfermedades autoinmunes.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- Las células T se someten a una selección timo para asegurar su correcto funcionamiento.
- Las células CD8 mal seleccionadas, que carecen del reconocimiento del receptor de células T (TCR) de la clase I del MHC, pueden escapar de la detección del timo.
- Existe una necesidad crítica de mecanismos posttimicos para eliminar tales células T potencialmente autorreactivas.
Objetivo del estudio:
- Definir un mecanismo de control de calidad posttimo que purgue las células CD8 mal seleccionadas.
- Para dilucidar los eventos moleculares que conducen a la eliminación de las células CD8 con TCR no funcionales.
- Comprender las implicaciones de los defectos en esta vía de control de calidad para las enfermedades autoinmunes.
Principales métodos:
- Análisis de las poblaciones de células CD8.
- Investigación del receptor de células T (TCR) y el compromiso del coreceptor CD8.
- Evaluación de los cambios en la expresión génica, incluida la inhibición del gen CD8 a través de la remetilación.
- Evaluación de la regulación de la superficie Fas y del ligando Fas.
- Inducción y análisis de la apoptosis celular.
Principales resultados:
- Las células CD8 mal seleccionadas no logran comprometer simultáneamente sus coreceptores TCR y CD8 con moléculas MHC.
- Esta falla inicia un proceso que involucra la inhibición de la expresión génica CD8 a través de la remetilación.
- El proceso culmina en la regulación hacia arriba de la superficie Fas y el ligando Fas, lo que lleva a la apoptosis.
- La continua coinversión de TCR-CD8 con MHC actúa como un punto de control de supervivencia.
Conclusiones:
- Una nueva vía de control de calidad posttimo elimina las células CD8 con TCR no funcionales.
- Esta vía se basa en el compromiso coordinado de TCR y el coreceptor CD8 con MHC.
- Los defectos moleculares en esta vía de señalización de la muerte contribuyen a la expansión de las células T doblemente negativas y las enfermedades autoinmunes sistémicas.
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