Publication: Función de CD69 en progenitores hematopoyéticos y la infección por el virus Vaccinia
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2018-08-23
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Universidad Complutense de Madrid
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Abstract
CD69 se expresa de manera temprana tras la activación leucocitaria y controla la migración linfocitaria y la secreción de citoquinas. En esta tesis, se ha estudiado la función de CD69 en la células hematopoyéticas progenitoras y en la infección por el virus Vaccinia. Durante la respuesta inmune frente a la infección viral, la proteína transmembrana CD69 es expresada en todas las células inmunitarias. En este trabajo, se ha estudiado el papel de CD69 en la respuesta inmune frente a la infección por el virus Vaccinia (VACV) en ratones, y se ha observado que la ausencia de CD69 mejora la protección contra VACV tanto a corto como a largo plazo en ratones inmunocompetentes e inmunodeficientes. Las células Natural Killer (NK) han sido involucradas a lo largo del tiempo con una mejor respuesta frente a la infección y en nuestro trabajo vemos que el aumento de células NK en ausencia de CD69 está relacionado con un aumento del control de la infección, ya que en estudios de eliminación de células NK, las diferencias no solo fueron abolidas sino que en este caso los ratones CD69-/- controlaban peor la infección. Este papel de las células NK no se basó en una reactividad alterada de las células NK, ya que CD69 no afectó al umbral de activación de las células NK en respuesta a MHC tipo I o a la activación de la proteína quinasa C. En cambio, el número de células NK aumentó en el bazo y peritoneo de ratones infectados deficientes para CD69. Esto no fue sólo secundario a un mejor control de la infección en ratones deficientes para CD69, ya que el número de células NK en bazo y sangre de ratones CD69-/- no infectados ya estaban aumentados. Las células NK deficientes en CD69 de ratones infectados no tenían una capacidad de proliferación alterada. Sin embargo, se observó una menor tasa de muerte celular espontánea para los linfocitos de ratones CD69-/-. Por lo tanto, nuestros resultados sugieren que CD69 controla la respuesta inmune innata a la infección por VACV, al menos en parte a través de una mayor supervivencia celular. Como acabamos de mencionar, los recuentos totales de células esplénicas se encontraron aumentados en ratones CD69-/- en estado basal y tras infección, y estos resultados están de acuerdo con los resultados anteriores de nuestro laboratorio [1] y podrían estar relacionados con la interacción de CD69 con S1P1. Además, hemos descrito que el tratamiento anti-CD69 simula en múltiples modelos la ausencia de CD69...
CD69 is early expressed upon leukocyte activation and controls lymphocyte trafficking and cytokine secretion. In this thesis, the function of CD69 was studied in hematopoietic progenitor cells and in Vaccinia virus infection. During the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to Vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69-/- mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69-/- lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival. As we have just shown above, total splenic cell counts were found increased in CD69-/- mice at steady state and after infection, and these results are in agreement with previous results of our laboratory [1]. As well, CD69 interacts with S1P1 which mediates leukocytes trafficking. Thus, we studied the possible role of CD69 targeting in leukocyte mobilization. As result, we described for the first time the capacity of anti-CD69 monoclonal antibodies (mAbs) to induce a rapid and massive egress of mature leukocytes as well as hematopoietic stem and progenitor stem cells (HSPC) from bone marrow, both in wild type mice treated with anti-mCD69 mAb and in transgenic huCD69 mice in CD69-/- background treated with anti-huCD69 mAb...
CD69 is early expressed upon leukocyte activation and controls lymphocyte trafficking and cytokine secretion. In this thesis, the function of CD69 was studied in hematopoietic progenitor cells and in Vaccinia virus infection. During the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to Vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69-/- mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69-/- lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival. As we have just shown above, total splenic cell counts were found increased in CD69-/- mice at steady state and after infection, and these results are in agreement with previous results of our laboratory [1]. As well, CD69 interacts with S1P1 which mediates leukocytes trafficking. Thus, we studied the possible role of CD69 targeting in leukocyte mobilization. As result, we described for the first time the capacity of anti-CD69 monoclonal antibodies (mAbs) to induce a rapid and massive egress of mature leukocytes as well as hematopoietic stem and progenitor stem cells (HSPC) from bone marrow, both in wild type mice treated with anti-mCD69 mAb and in transgenic huCD69 mice in CD69-/- background treated with anti-huCD69 mAb...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 12-06-2017