title: Critical roles for Rac GTPases in T-cell migration to and within lymph nodes.
abstract: Naive T cells continuously recirculate between secondary lymphoid tissue via the blood and lymphatic systems, a process that maximizes the chances of an encounter between a T cell and its cognate antigen. This recirculation depends on signals from chemokine receptors, integrins, and the sphingosine-1-phosphate receptor. The authors of previous studies in other cell types have shown that Rac GTPases transduce signals leading to cell migration and adhesion; however, their roles in T cells are unknown. By using both 3-dimensional intravital and in vitro approaches, we show that Rac1- and Rac2-deficient T cells have multiple defects in this recirculation process. Rac-deficient T cells home very inefficiently to lymph nodes and the white pulp of the spleen, show reduced interstitial migration within lymph node parenchyma, and are defective in egress from lymph nodes. These mutant T cells show defective chemokine-induced chemotaxis, chemokinesis, and adhesion to integrin ligands. They have reduced lateral motility on endothelial cells and transmigrate in-efficiently. These multiple defects stem from critical roles for Rac1 and Rac2 in transducing chemokine and sphingosine-1-phosphate receptor 1 signals leading to motility and adhesion.
authors.affiliation: Medical Research Council National Institute for Medical Research, London, UK.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Faroudi
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hons
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zachacz
authors.forename: Celine
authors.initials: C
authors.lastname: Dumont
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D019426:Integrases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D018925:Chemokines; D019426:Integrases; D016023:Integrins; D009479:Neuropeptides; D019707:Receptors, Chemokine; D049349:Receptors, Lysosphingolipid; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse; C045073:Cre recombinase