TY - JOUR
T1 - A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress
AU - Nombela-Arrieta, César
AU - Mempel, Thorsten R.
AU - Soriano, Silvia F.
AU - Mazo, Irina
AU - Wymann, Matthias P.
AU - Hirsch, Emilio
AU - Martínez-A., Carlos
AU - Fukui, Yoshinori
AU - Von Andrian, Ulrich H.
AU - Stein, Jens V.
PY - 2007/3/19
Y1 - 2007/3/19
N2 - 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
AB - 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
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U2 - 10.1084/jem.20061780
DO - 10.1084/jem.20061780
M3 - Article
C2 - 17325199
AN - SCOPUS:33947411398
VL - 204
SP - 497
EP - 510
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 3
ER -