Regulatory role of semaforin-3A in the development of human T cells: inibitory effect on the migration of thymocytes mediated by the CXCL12.
The thymus is the primary lymphoid organ, responsible for normal T cell development in vertebrates. This is a highly complex process that includes cell proliferation, death, migration as well as T cell receptor gene rearrangements. It takes place within the thymic lobules and depends on several types of interactions between developing thymocytes and the thymicmicroenvironment. Along with differentiation, thymocytes migrate within the thymic parenchyma: bone marrow-derived precursors arriving in the organ migrate towards the sub-capsular cortex, and from this niche, differentiation progresses in parallel with migration from the cortex to themedulla of thymic lobules, where positively selected mature cells are located, before leaving the organ. Such oriented movements are tightly regulated by a number of interactions including those mediated extracellular matrix and by chemokines. Among the various chemokines, CXCL12 plays a major role in intrathymic T cell migration. More recently it was showed in our Laboratory that the semaphorin-3A (Sema-3A), a soluble member of the semaphorin family (well described in the nervous system as being important for axonal guidance) is also involved in human thymocyte migration, bearing a chemorepulsive and de-adhesive role. Herein, we studied the role of Sema-3A upon the CXCL12-driven migration of humanthymocytes. We showed that, in addition to the proper chemorepulsive activity upon thymocyte subsets, Sema-3A is able to impair the chemoattraction (and even the chemorepulsion) triggered by CXCL12, thus acting as a physiological antagonist for this chemokine-drivenmigration. At least in part, this inhibitory effect of Sema-3A can be explained by their capacity to modify the phosphorylation status of intracellular signally proteins, including ERK-1/2, FAK and Zap-70. Also, Sema-3A partially block the conjoint effect of CXCL12 plus fibronectin upon thymocyte migration.Taken together, our results demonstrate the involvement of Sema-3A in the regulation of chemokine-driven human thymocyte migration. Moreover, they provide new clues for better understanding the complexity of cell migration, unraveling a novel physiological connectivity between distinct cell migration-related molecular interactions.
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Date of Publication:04/14/2008