Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners.
The small GTPase Rap1 and its effector RAPL regulate lymphocyte adhesion and motility. However, their precise regulatory roles in the adhesion cascade preceding entry into lymph nodes and during interstitial migration are unclear. Here, we show that Rap1 is indispensably required for the chemokine-triggered initial arrest step of rolling lymphocytes through LFA-1, whereas RAPL is not involved in rapid arrest. RAPL and talin play a critical role in stabilizing lymphocyte arrest to the endothelium of blood vessels under flow or to the high endothelial venules of peripheral lymph nodes in vivo. Further, mutagenesis and peptide studies suggest that release of a trans-acting restraint from the beta2 cytoplasmic region of LFA-1 is critical for Rap1-dependent initial arrest. Rap1 or RAPL deficiency severely impaired lymphocyte motility over lymph node stromal cells in vitro, and RAPL deficiency impaired high-velocity directional movement within lymph nodes. These findings reveal the several critical steps of Rap1, which are RAPL-dependent and -independent, in lymphocyte trafficking.
Ebisuno
Yukihiko
Y
Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Monguchi, Japan.
Katagiri
Koko
K
Katakai
Tomoya
T
Ueda
Yoshihiro
Y
Nemoto
Tomomi
T
Inada
Hiroyuki
H
Nabekura
Junichi
J
Okada
Takaharu
T
Kannagi
Reiji
R
Tanaka
Toshiyuki
T
Miyasaka
Masayuki
M
Hogg
Nancy
N
Kinashi
Tatsuo
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D036904:Leukocyte Rolling / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology; D016608:Talin / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins
D000911:Antibodies, Monoclonal; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D016608:Talin; D020827:rap1 GTP-Binding Proteins; C455831:Rassf5 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins