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

Nombela-Arrieta, César; Mempel, Thorsten R; Soriano, Silvia F; Mazo, Irina; Wymann, Matthias P; Hirsch, Emilio; Martínez-A, Carlos; Fukui, Yoshinori; von Andrian, Ulrich H; Stein, Jens V (2007). A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress. Journal of experimental medicine, 204(3), pp. 497-510. New York, N.Y.: Rockefeller University Press 10.1084/jem.20061780

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Recent observations using multiphoton intravital microscopy (MP-IVM) have uncovered an unexpectedly high lymphocyte motility within peripheral lymph nodes (PLNs). Lymphocyte-expressed 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 (PI3K)gamma, signaling molecules that act downstream of G protein-coupled receptors, including chemokine receptors (CKRs). T and B cells lacking DOCK2 alone or DOCK2 and PI3Kgamma displayed markedly reduced motility inside T cell area and B cell follicle, respectively. Lack of PI3Kgamma 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 G(alphai) protein-coupled receptor similar to CKR, we further analyzed whether DOCK2 and PI3Kgamma contributed to S1P-triggered signaling events. S1P-induced cell migration was significantly reduced in T and B cells lacking DOCK2, whereas T cell-expressed PI3Kgamma contributed to F-actin polymerization and protein kinase B phosphorylation but not migration. These findings correlated with delayed lymphocyte egress from PLNs in the absence of DOCK2 but not PI3Kgamma, and a markedly reduced cell motility of DOCK2-deficient 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 PI3Kgamma, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
UniBE Contributor:	Stein, Jens Volker
ISSN:	0022-1007
ISBN:	17325199
Publisher:	Rockefeller University Press
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:55
Last Modified:	05 Dec 2022 14:17
Publisher DOI:	10.1084/jem.20061780
PubMed ID:	17325199
Web of Science ID:	000245210800012
URI:	https://boris.unibe.ch/id/eprint/23662 (FactScience: 43330)