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

César Nombela-Arrieta, Thorsten R. Mempel, Silvia F. Soriano, Irina Mazo, Matthias P. Wymann, Emilio Hirsch, Carlos Martínez-A., Yoshinori Fukui, Ulrich H. Von Andrian, Jens V. Stein

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Abstract

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)γ, signaling molecules that act downstream of G protein-coupled receptors, including chemokine receptors (CKRs). T and B cells lacking DOCK2 alone or DOCK2 and PI3Kγ displayed markedly reduced motility inside T cell area and B cell follicle, respectively. Lack of PI3Kγ 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 αi protein-coupled receptor similar to CKR, we further analyzed whether DOCK2 and PI3Kγ contributed to S1P-triggered signaling events. S1P-induced cell migration was significantly reduced in T and B cells lacking DOCK2, whereas T cell-expressed PI3Kγ 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 PI3Kγ, 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 PI3Kγ, for signal transduction during interstitial lymphocyte migration and S1P-mediated egress. JEM

Original languageEnglish
Pages (from-to)497-510
Number of pages14
JournalJournal of Experimental Medicine
Volume204
Issue number3
DOIs
Publication statusPublished - Mar 19 2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Nombela-Arrieta, C., Mempel, T. R., Soriano, S. F., Mazo, I., Wymann, M. P., Hirsch, E., Martínez-A., C., Fukui, Y., Von Andrian, U. H., & Stein, J. V. (2007). A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress. Journal of Experimental Medicine, 204(3), 497-510. https://doi.org/10.1084/jem.20061780