Publication: Papel del TCR en el desarrollo y función de los linfocitos Tϒδ efectores
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2017-05-16
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Universidad Complutense de Madrid
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Abstract
Las células Tγδ se han revelado en los últimos tiempos como un tipo celular básico dentro del sistema inmunológico innato y adaptativo por su capacidad para producir citoquinas a diferentes tiempos y a la posibilidad de actuar contra distintos agentes infecciosos como virus, bacterias, parásitos o incluso contra células tumorales. Las distintas subpoblaciones de linfocitos Tγδ con capacidad de producir IFN-γ o IL-17 principalmente, se generan en el timo de ratón, pero los estados de maduración o señales que dirigen y controlan este proceso de diferenciación no se conocen con exactitud. En este contexto, el TCR parece ser clave para entender el desarrollo de estos linfocitos Tγδ. Se acepta, gracias a diferentes estudios, que las células que reciben una intensidad de señal fuerte a través del TCR son aquellas que tendrán capacidad para producir IFN-γ, mientras que las células que producen IL-17 emergerán por “defecto” durante el desarrollo tímico recibiendo únicamente una señal débil a través del TCR. Sin embargo, este modelo ha sido discutido en los últimos dos años, pues se ha descrito que las células Tγδ del ratón SKG (ratón con una mutación hipomórfica en ZAP-70 que reduce en torno al 90% la capacidad de señalización vía TCR)mantienen intacta su capacidad para producir IFN-γ. No obstante, sí ven afectada la producción de IL-17 (tanto en timo como en periferia). Además otros artículos relacionaron el cambioconformacional del TCR tras activación con el desarrollo de algunas células Tγδ productoras de IL-17. En este punto, nos planteamos abordar esta cuestión desde una perspectiva diferente:disminuir la cantidad de TCRγδ en la superficie celular con el fin de interferir su señalización invivo. Para ello, se generaron y analizaron ratones portadores de mutaciones que afectaban la expresión de CD3γ, CD3δ y CD3ɛ, sin observarse diferencias significativas comparando con ratones control. Sin embargo, cuando se analizó un ratón con haploinsuficiencia simultanea para Cd3g y Cd3d (CD3DH, por Haploinsuficiencia Doble de Cd3), se pudo comprobar cómo efectivamente la expresión del TCRγδ en superficie se encontraba disminuida, pero no la del TCRαβ. Por lo tanto, se consideró que este ratón (la menor expresión del TCRγδ en superficie también implica una menor capacidad de señalización) podría ser una herramienta útil para entender el papel que juega la intensidad de la señal del TCR en el desarrollo de las distintas subpoblaciones efectoras de células Tγδ en el timo. Cabe destacar que este modelo de ratón permite abordar esta pregunta sobre el repertorio total de linfocitos Tγδ (policlonal) y no desde un abordaje monoclonal (ratones transgénicos que expresan un único TCR), como se había descrito en la mayoría de los trabajos relacionados con el tema...
The γδ T cells have recently emerged as a basic cell type within the innate and adaptive immune system, due to their ability to produce cytokines at different time points and to act against various infectious agents such as viruses, bacteria, parasites or even against tumour cells. The different subpopulations of γδ T lymphocytes that are able to produce mainly IFN-γ or IL-17 are generated in the mouse thymus, but the maturation states or the signals that manage and control this differentiation process are still unknown. In this context, the TCR appears as a key element to understand the γδ T lymphocytes development. Thanks to various studies, it is generally accepted/Several studies have shown that cells receiving strong signals through the TCR will have the capacity to produce IFN-γ, while cells that produce IL-17 emerge by default during T cell development just by receiving weak TCR signals. However, this model has been discussed in the last two years because it has been described that γδ T cells from the SKG mouse (mouse with a hypomorphic mutation in ZAP-70 that reduces the TCR signalling capacity by around 90%) maintain the capacity to produce IFN γ. However, the production of IL-17 is affected (in both thymus and periphery). Also, other works related the TCR conformational change following activation with the development of IL-17producing cells. At this point, we planned to address this issue from a different point of view: bydecreasing the amount of TCRγδ in the cell surface in order to interfere the signalling in vivo.For/to achieve this aim, mice carrying mutations that affect the expression of CD3γ, CD3δ and CD3ɛ were generated and analysed, but we found no significant differences when compared to control mice. However, when a mouse with simultaneous haploinsufficiency for Cd3g and Cd3d (CD3DH, for CD3 Double Haploinsufficiency) was analysed, we found that the surface expression of TCRγδ was reduced, but not that of TCRαβ. Therefore, we considered that this mouse (the lower expression of surface TCRγδ also implies less signalling capacity) can be a useful tool to understand the role of TCR signal strength in the thymic differentiation of discrete proinflammatory γδ T cell subsets. Note that this mouse model could address this question on the total γδ T cells repertoire (polyclonal), not only from a monoclonal approach using transgenic mice expressing a single TCR (like it has been described in most of the related work)...
The γδ T cells have recently emerged as a basic cell type within the innate and adaptive immune system, due to their ability to produce cytokines at different time points and to act against various infectious agents such as viruses, bacteria, parasites or even against tumour cells. The different subpopulations of γδ T lymphocytes that are able to produce mainly IFN-γ or IL-17 are generated in the mouse thymus, but the maturation states or the signals that manage and control this differentiation process are still unknown. In this context, the TCR appears as a key element to understand the γδ T lymphocytes development. Thanks to various studies, it is generally accepted/Several studies have shown that cells receiving strong signals through the TCR will have the capacity to produce IFN-γ, while cells that produce IL-17 emerge by default during T cell development just by receiving weak TCR signals. However, this model has been discussed in the last two years because it has been described that γδ T cells from the SKG mouse (mouse with a hypomorphic mutation in ZAP-70 that reduces the TCR signalling capacity by around 90%) maintain the capacity to produce IFN γ. However, the production of IL-17 is affected (in both thymus and periphery). Also, other works related the TCR conformational change following activation with the development of IL-17producing cells. At this point, we planned to address this issue from a different point of view: bydecreasing the amount of TCRγδ in the cell surface in order to interfere the signalling in vivo.For/to achieve this aim, mice carrying mutations that affect the expression of CD3γ, CD3δ and CD3ɛ were generated and analysed, but we found no significant differences when compared to control mice. However, when a mouse with simultaneous haploinsufficiency for Cd3g and Cd3d (CD3DH, for CD3 Double Haploinsufficiency) was analysed, we found that the surface expression of TCRγδ was reduced, but not that of TCRαβ. Therefore, we considered that this mouse (the lower expression of surface TCRγδ also implies less signalling capacity) can be a useful tool to understand the role of TCR signal strength in the thymic differentiation of discrete proinflammatory γδ T cell subsets. Note that this mouse model could address this question on the total γδ T cells repertoire (polyclonal), not only from a monoclonal approach using transgenic mice expressing a single TCR (like it has been described in most of the related work)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 15/07/2016