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Title

A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate–mediated egress

AuthorsNombela-Arrieta, César; Mempel, Thorsten R.; Soriano, Silvia F.; Mazo, Irina; Wymann, Matthias P.; Hirsch, Emilio; Martínez-Alonso, Carlos; Fukui, Yoshinori; Andrian, Ulrich H. von; Stein, Jens V.
KeywordsHematology
Issue DateMar-2007
PublisherRockefeller University Press
CitationThe Journal of Experimental Medicine, Vol. 204, No. 3, March 19, 2007, pp. 497–510
AbstractRecent observations using multiphoton intravital microscopy (MP-IVM) have uncovered an unexpectedly high lymphocyte motility within peripheral lymph nodes (PLNs). Lymphocyteexpressed intracellular signaling molecules governing interstitial movement remain largely unknown. Here, we used MP-IVM of murine PLNs to examine interstitial motility of lymphocytes lacking the Rac guanine exchange factor DOCK2 and phosphoinositide-3-kinase (PI3Kƴ), signaling molecules that act downstream of G protein–coupled receptors, including chemokine receptors (CKRs). T and B cells lacking DOCK2 alone or DOCK2 and PI3Kƴ displayed markedly reduced motility inside T cell area and B cell follicle, respectively. Lack of PI3Kƴ alone had no effect on migration velocity but resulted in increased turning angles of T cells. As lymphocyte egress from PLNs requires the sphingosine-1-phosphate (S1P) receptor 1, a Gi protein–coupled receptor similar to CKR, we further analyzed whether DOCK2 and PI3Kƴ contributed to S1P-triggered signaling events. S1P-induced cell migration was signifi cantly reduced in T and B cells lacking DOCK2, whereas T cell–expressed PI3Kƴ contributed to F-actin polymerization and protein kinase B phosphorylation but not migration. These fi ndings correlated with delayed lymphocyte egress from PLNs in the absence of DOCK2 but not PI3K, and a markedly reduced cell motility of DOCK2-defi cient T cells in close proximity to efferent lymphatic vessels. In summary, our data support a central role for DOCK2, and to a lesser extent T cell–expressed PI3Kƴ, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress.
DescriptionCopyright by The Rockefeller University Press
URIhttp://hdl.handle.net/10261/3237
DOI10.1084/jem.20061780
ISBN1540-9538
Appears in Collections:(CNB) Artículos




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