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 language | English |
|---|---|
| Pages (from-to) | 497-510 |
| Number of pages | 14 |
| Journal | Journal of Experimental Medicine |
| Volume | 204 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 19 2007 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology
Cite this
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.
In: Journal of Experimental Medicine, Vol. 204, No. 3, 19.03.2007, p. 497-510.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=33947411398&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33947411398&partnerID=8YFLogxK
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 -