The Journal of Experimental Medicine
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Published online February 26, 2007
doi:10.1084/jem.20061780
The Journal of Experimental Medicine, Vol. 204, No. 3, 497-510
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Nombela-Arrieta et al.
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ARTICLE

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

César Nombela-Arrieta1, Thorsten R. Mempel2, Silvia F. Soriano1, Irina Mazo2, Matthias P. Wymann3, Emilio Hirsch4, Carlos Martínez-A.5, Yoshinori Fukui6, Ulrich H. von Andrian2, and Jens V. Stein1

1 Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland
2 The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Department of Clinical Biological Sciences, Institute of Biochemistry and Genetics, University of Basel, CH-4003 Basel, Switzerland
4 Department of Genetics, Biology and Biochemistry, University of Turin, 10060 Turin, Italy
5 Department of Immunology and Oncology, National Center for Biotechnology-CSIC, 28049 Madrid, Spain
6 PRESTO, Japan Science and Technology Agency, and Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

CORRESPONDENCE Jens V. Stein: jstein{at}tki.unibe.ch

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 PI3K{gamma} displayed markedly reduced motility inside T cell area and B cell follicle, respectively. Lack of PI3K{gamma} 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{alpha}i protein–coupled receptor similar to CKR, we further analyzed whether DOCK2 and PI3K{gamma} contributed to S1P-triggered signaling events. S1P-induced cell migration was significantly reduced in T and B cells lacking DOCK2, whereas T cell–expressed PI3K{gamma} 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 PI3K{gamma}, 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 PI3K{gamma}, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress.

Abbreviations used: ANOVA, analysis of variance; CKR, chemokine receptor; GPCR, G protein–coupled receptor; HEV, high endothelial venule; MP-IVM, multiphoton intravital microscopy; o.n., overnight; PI3K, phosphoinositide-3-kinase; PKB, protein kinase B; PLN, peripheral lymph node; RGS, regulator of G protein signaling; S1P, sphingosine-1-phosphate; SLO, secondary lymphoid organ; WGA, wheat germ agglutinin.

C. Nombela-Arrieta and T.R. Mempel contributed equally to this work.


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