Critical roles for Rac GTPases in T-cell migration to and within lymph nodes.
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.
Faroudi
Mustapha
M
Medical Research Council National Institute for Medical Research, London, UK.
Hons
Miroslav
M
Zachacz
Agnieszka
A
Dumont
Celine
C
Lyck
Ruth
R
Stein
Jens V
JV
Tybulewicz
Victor L J
VL
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
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