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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-03-0841. This Article Full Text (PDF) All Versions of this Article: 2002-03-0841v1 101/1/38    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stein, J. V Articles by Martinez-A., C. Search for Related Content PubMed PubMed Citation Articles by Stein, J. V Articles by Martinez-A., C. Social Bookmarking                   What's this? Submitted March 20, 2002 Accepted June 17, 2002 CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway Jens V Stein*, Silvia F Soriano, Christine M'rini, Cesar Nombela-Arrieta, Gonzalo Gonzalez de Buitrago, Jose Miguel Rodriguez-Frade, Mario Mellado, Jean-Philippe Girard, and Carlos Martinez-A. Immunology and Oncology, Centro Nacional de Biotecnolgia-CSIC, Madrid, Spain Laboratoire de Physiologie, Faculte de Medecine de Rangueil, Toulouse, France; Unite de Microscopie Intravitale, Laboratoire de Biologie Vasculaire, IPBS/CNRS-UPR9062, Toulouse, France Unite de Microscopie Intravitale, Laboratoire de Biologie Vasculaire, IPBS/CNRS-UPR9062, Toulouse, France * Corresponding author; email: jstein{at}cnb.uam.es. Homing of blood-borne lymphocytes to peripheral lymph nodes (PLN) is a multi-step process dependent on the sequential engagement of L-selectin, which mediates lymphocyte rolling along the luminal surface of high endothelial venules (HEV), followed by activation of lymphocyte integrins, and transmigration through HEV. Within lymphoid tissue, B and T lymphocytes then migrate towards specific microenvironments such as B cell follicles and paracortex, respectively. The lymphocyte-expressed chemokine receptor CCR7 is playing an important role during this process, as its HEV-presented ligands CCL19 and CCL21 can trigger rapid integrin activation under flow, in addition to inducing a chemotactic response which may participate in transmigration and/or interstitial migration. Here, we report that Tyrphostin (Tyr) AG490, a pharmacological inhibitor of Janus family tyrosine kinases (Jak), blocked the chemotactic response of primary mouse lymphocytes to CCL19 and CCL21 in a dose-dependent manner. Furthermore, Tyr AG490 inhibited rapid CCL21-mediated upregulation of alpha 4 and beta 2 integrin adhesiveness in static adhesion assays and under physiological flow, whereas adhesion induced by Phorbol-12-Myristate-13-Acetate (PMA) remained unaltered. Using intravital microscopy of subiliac PLN in mice, we found that adoptively transferred Tyr AG490-treated lymphocytes adhered significantly less in HEV as compared to control cells, although L-selectin-mediated rolling was similar between both samples. Finally, we observed a rapid increase in phosphorylated Jak2 in CCL21-stimulated primary mouse lymphocytes. Thus, our study suggests a role for Jak tyrosine kinases during CCR7-mediated lymphocyte recirculation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Xu, K. Aoyama, M. Kusumoto, A. Matsuzawa, E. C. Butcher, S. A. Michie, T. Matsuyama, and T. 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