TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity.
Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper 1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but it reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 immunoglobulin variable domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease.
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Stefano
S
Angiari
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Tiziano
T
Donnarumma
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Barbara
B
Rossi
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Silvia
S
Dusi
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Enrica
E
Pietronigro
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Elena
E
Zenaro
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Vittorina
V
Della Bianca
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy; The Center for Biomedical Computing (CBMC), University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Lara
L
Toffali
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Gennj
G
Piacentino
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Simona
S
Budui
Department of Molecular Discovery and Immunobiology, Biogen Idec Inc., 12 Cambridge Center, Cambridge, MA 02146, USA.
Paul
P
Rennert
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 785, Boston, MA 02115-5817, USA.
Sheng
S
Xiao
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy; The Center for Biomedical Computing (CBMC), University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
Carlo
C
Laudanna
Centro Nacional de Biotecnología, CNB-CSIC, Campus UAM, C/ Darwin, 3, Campus of Cantoblanco, E-28049 Madrid, Spain.
Jose M
JM
Casasnovas
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 785, Boston, MA 02115-5817, USA.
Vijay K
VK
Kuchroo
Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy. Electronic address: gabriela.constantin@univr.it.
Gabriela
G
Constantin
D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D006967:Hypersensitivity / Q000276:immunology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D019007:P-Selectin / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D019007:P-Selectin; C084882:P-selectin ligand protein; D010446:Peptide Fragments; C517781:myelin oligodendrocyte glycoprotein (34-56)