Rap1 and its effector RIAM are required for lymphocyte trafficking.
Regulation of integrins is critical for lymphocyte adhesion to endothelium and trafficking through secondary lymphoid organs. Inside-out signaling to integrins is mediated by the small GTPase Rap1. Two effectors of Rap1 regulate integrins, RapL and Rap1 interacting adaptor molecule (RIAM). Using mice conditionally deficient in both Rap1a and Rap1b and mice null for RIAM, we show that the Rap1/RIAM module is not required for T- or B-cell development but is essential for efficient adhesion to intercellular adhesion molecule (ICAM) 1 and vascular cell adhesion molecule (VCAM) 1 and for proper trafficking of lymphocytes to secondary lymphoid organs. Interestingly, in RIAM-deficient mice, whereas peripheral lymph nodes (pLNs) were depleted of both B and T cells and recirculating B cells were diminished in the bone barrow (BM), the spleen was hypercellular, albeit with a relative deficiency of marginal zone B cells. The abnormality in lymphocyte trafficking was accompanied by defective humoral immunity to T-cell-dependent antigens. Platelet function was intact in RIAM-deficient animals. These in vivo results confirm a role for RIAM in the regulation of some, but not all, leukocyte integrins and suggest that RIAM-regulated integrin activation is required for trafficking of lymphocytes from blood into pLNs and BM, where relatively high shear forces exist in high endothelial venules and sinusoids, respectively.
Perlmutter Cancer Institute and.
Wenjuan
W
Su
Department of Medicine, University of Chicago, Chicago, IL;
Joseph
J
Wynne
Immune Modulatory Receptor/Oncology, Merck Research Laboratories, Boston, MA;
Elaine M
EM
Pinheiro
Department of Medicine, New York University School of Medicine, New York, NY;
Marianne
M
Strazza
Department of Medicine, New York University School of Medicine, New York, NY;
Adam
A
Mor
Department of Medicine, New York University School of Medicine, New York, NY;
Emilie
E
Montenont
Department of Medicine, New York University School of Medicine, New York, NY;
Jeffrey
J
Berger
McAllister Heart Institute and.
David S
DS
Paul
McAllister Heart Institute and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC; and.
Wolfgang
W
Bergmeier
Koch Institute, Massachusetts Institute of Technology, Cambridge, MA.
Frank B
FB
Gertler
Perlmutter Cancer Institute and Department of Medicine, New York University School of Medicine, New York, NY;
Mark R
http://orcid.org/0000-0002-1179-8156
MR
Philips
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D008565:Membrane Proteins; C521189:RIAM protein, mouse; D020827:rap1 GTP-Binding Proteins