Rol del heterómero CCR9:DRDS en la migración de linfocitos T CD4+
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Fecha
2021
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Las enfermedades inflamatorias intestinales son un conjunto de patologías que están
caracterizadas por una desregulación de la respuesta inmune y una reducción de los
niveles homeostáticos de dopamina en el tracto digestivo. Este desbalance se debe
principalmente a un cambio en las subpoblaciones de linfocitos T CD4+ efectores y
reguladores que mantienen una respuesta controlada en contra de la microbiota
intestinal. La disminución de los niveles de dopamina favorece la diferenciación y
expansión linfocitaria de los fenotipos inflamatorios Th1 y Th17. Además, durante la
progresión de estas patologías, se produce un aumento de la migración linfocitaria
hacia las zonas de inflamación, promovida por un aumento de la producción de
MAdCAM-1 y CCL25 en el colon, ligandos de la integrina a4b7 y el receptor acoplado
a proteína G, CCL25, respectivamente. Con respecto a esto, hemos observado que
ratones linfopénicos reconstituidos con linfocitos T CD4 + carentes del receptor D5 de
dopamina (DRD5) son resistentes a la colitis crónica inducida por la transferencia
adoptiva de células T vírgenes. Los linfocitos transferidos migran de forma poco
eficiente al colon a pesar de mantener una expresión elevada de la molécula CCR9.
En este contexto, nuestro laboratorio ha sugerido la existencia de heterómeros
formados por CCR9 y DRD5 en las células T CD4 + que infiltran la mucosa intestinal
en condiciones de colitis inflamatoria en ratón. A través de ensayos de BRET y de
ligación por proximidad, hemos observado que tanto CCR9 como el DRD5 se expresan
en estrecha proximidad en la membrana de células Jurkat transducidas con dichas
proteínas o en células T CD4+ efectoras en el colon de ratones en un modelo de colitis
crónica. Finalmente, observamos que, si interrumpíamos la formación del heterómero
con péptidos análogos a los segmentos transmembrana involucrados en la interface
de interacción entre ambos receptores, los linfocitos T CD4 + con tropismo intestinal
pierden su capacidad migratoria hacia el colon. De esta forma, creemos que el
heterómero conformado por CCR9: DRDS actuaría de manera distinta a los
protómeros que lo conforman, promoviendo la migración linfocitaria hacia el colon en
condiciones de inflamación intestinal.
Inflammatory bowel diseases are a group of pathologies characterized by a deregulation in the immune response and a decrease in the homeostatic levels of dopamine in the gastrointestinal tract. This effect is mediated by a change in the balance of regulatory or effector co4+ T Cell subpopulations, which maintain a controlled response toward intestinal microbiota. Lower dopamine levels induce the expansion and differentiation of the inflammatory phenotypes Thl and Th17. Moreover, during disease progression, there is an increase in the lymphocytic migration towards inflamed tissues prometed by the overexpr1=ssion of MAdCAM-1 and CCL25 in the colonic epithelium, which are the ligands for integrin a4137 and the G-coupled receptor, CCL25, respectively. Related to this, we have observed that limphopenic mice which have been reconstituted with dopamine receptor D5 (DRDS) knock out co4+ T cells, are protected against the chronic model of colitis induced by na'ive T cells. Transferred lymphocytes migrate poorly towards the intestine in spite of maintaining an elevated expression of the molecule CCR9. In this context, our laboratory suggested that CCR9 and DRDS form a heteromer in the membrane of co4+ T cells that infiltrate intestinal mucosa in mice suffering from inflammatory colitis. We have observed by bioluminescence resonance energy transfer (BRET) and proximity ligation assay (PLA) thar CCR9 and DRDS are expressed in close proximity in the membrane of transfected Jurkat cells or in effector co4+ T cells located in the intestine of mice in a chronic colitis model. Finally, we observed that, if we interrupted heteromer formation with peptides analog to the transmembrane segments involved in the interaction between CCR9 or DRDS, co4+ T cells with intestinal tropism lose their ability to migrate towards the intestine. Thus, we believe that the heteromer formed by CCR9 and DRDS act in an independent way of each one of its promoters, promoting the lymphocytic migration towards the intestine in intestinal inflammatory conditions.
Inflammatory bowel diseases are a group of pathologies characterized by a deregulation in the immune response and a decrease in the homeostatic levels of dopamine in the gastrointestinal tract. This effect is mediated by a change in the balance of regulatory or effector co4+ T Cell subpopulations, which maintain a controlled response toward intestinal microbiota. Lower dopamine levels induce the expansion and differentiation of the inflammatory phenotypes Thl and Th17. Moreover, during disease progression, there is an increase in the lymphocytic migration towards inflamed tissues prometed by the overexpr1=ssion of MAdCAM-1 and CCL25 in the colonic epithelium, which are the ligands for integrin a4137 and the G-coupled receptor, CCL25, respectively. Related to this, we have observed that limphopenic mice which have been reconstituted with dopamine receptor D5 (DRDS) knock out co4+ T cells, are protected against the chronic model of colitis induced by na'ive T cells. Transferred lymphocytes migrate poorly towards the intestine in spite of maintaining an elevated expression of the molecule CCR9. In this context, our laboratory suggested that CCR9 and DRDS form a heteromer in the membrane of co4+ T cells that infiltrate intestinal mucosa in mice suffering from inflammatory colitis. We have observed by bioluminescence resonance energy transfer (BRET) and proximity ligation assay (PLA) thar CCR9 and DRDS are expressed in close proximity in the membrane of transfected Jurkat cells or in effector co4+ T cells located in the intestine of mice in a chronic colitis model. Finally, we observed that, if we interrupted heteromer formation with peptides analog to the transmembrane segments involved in the interaction between CCR9 or DRDS, co4+ T cells with intestinal tropism lose their ability to migrate towards the intestine. Thus, we believe that the heteromer formed by CCR9 and DRDS act in an independent way of each one of its promoters, promoting the lymphocytic migration towards the intestine in intestinal inflammatory conditions.
Notas
Tesis (Doctor en Biotecnología)
Palabras clave
Enfermedades Inflamatorias Intestinales, Receptores de Dopamina, Linfocitos T CD4-Positivos