title: Janus kinases 1 and 2 regulate chemokine-mediated integrin activation and naïve T-cell homing.
abstract: Janus kinases (JAKs) are central signaling molecules in cytokine receptor cascades. Although they have also been implicated in chemokine receptor signaling, this function continues to be debated. To address this issue, we established a nucleofection model in primary, nonactivated mouse T lymphocytes to silence JAK expression and to evaluate the ability of these cells to home to lymph nodes. Reduced JAK1 and JAK2 expression impaired naïve T-cell migration in response to gradients of the chemokines CXCL12 and CCL21. In vivo homing of JAK1/JAK2-deficient cells to lymph nodes decreased, whereas intranodal localization and motility were unaffected. JAK1 and JAK2 defects altered CXCL12- and CCL21-triggered ezrin/radixin/moesin (ERM) dephosphorylation and F-actin polymerization, as well as activation of lymphocyte function-associated Ag-1 and very late Ag-4 integrins. As a result, the cells did not adhere firmly to integrin substrates in response to these chemokines. The results demonstrate that JAK1/JAK2 participate in chemokine-induced integrin activation and might be considered a target for modulation of immune cell extravasation and therefore, control of inflammatory reactions.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Pérez-Rivero
authors.forename: Graciela
authors.initials: G
authors.lastname: Cascio
authors.forename: Silvia Fernández
authors.initials: SF
authors.lastname: Soriano
authors.forename: Álvaro Gil
authors.initials: ÁG
authors.lastname: Sanz
authors.forename: Julia Sáez
authors.initials: JS
authors.lastname: de Guinoa
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Rodríguez-Frade
authors.forename: Rosa P
authors.initials: RP
authors.lastname: Gomariz
authors.forename: Borja L
authors.initials: BL
authors.lastname: Holgado
authors.forename: Carlos
authors.initials: C
authors.lastname: Cabañas
authors.forename: Yolanda R
authors.initials: YR
authors.lastname: Carrasco
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005260:Female; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000276:immunology / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058105:Polymerization; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D000199:Actins; D018925:Chemokines; D016023:Integrins; D034741:RNA, Small Interfering; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: Chemokine receptor; Integrin; Janus kinase; Lymphocyte homing