TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity

  • Immunity. 2014 Apr 17;40(4):542-53. doi: 10.1016/j.immuni.2014.03.004.
Stefano Angiari  1 ,  Tiziano Donnarumma  1 ,  Barbara Rossi  1 ,  Silvia Dusi  1 ,  Enrica Pietronigro  1 ,  Elena Zenaro  1 ,  Vittorina Della Bianca  1 ,  Lara Toffali  2 ,  Gennj Piacentino  1 ,  Simona Budui  1 ,  Paul Rennert  3 ,  Sheng Xiao  4 ,  Carlo Laudanna  2 ,  Jose M Casasnovas  5 ,  Vijay K Kuchroo  4 ,  Gabriela Constantin  6
Affiliations
  • 1. Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
  • 2. 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.
  • 3. Department of Molecular Discovery and Immunobiology, Biogen Idec Inc., 12 Cambridge Center, Cambridge, MA 02146, USA.
  • 4. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 785, Boston, MA 02115-5817, USA.
  • 5. Centro Nacional de Biotecnología, CNB-CSIC, Campus UAM, C/ Darwin, 3, Campus of Cantoblanco, E-28049 Madrid, Spain.
  • 6. Department of Pathology and Diagnostics, University of Verona, Strada le Grazie 8, 37134 Verona, Italy. Electronic address: [email protected].
PMID: 24703780 DOI: 10.1016/j.immuni.2014.03.004
Abstract

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.