title: Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes.
abstract: Effective stimulation of CD4+ T cells in an immune response depends on activation signals transduced via not only the CD3-T-cell receptor (TCR) complex but also those generated by accessory cell-surface proteins, including some that mediate adhesion between T cells and antigen-presenting cells (APC). Three members of the Ig superfamily, CD54 [intercellular cell adhesion molecule 1 (ICAM-1)], CD58 [lymphocyte function-associated antigen 3 (LFA-3)], and B7, expressed on the surface of APC, have been shown to mediate both adhesion and signaling during T cell-APC interactions. Recently another member of the Ig superfamily, [vascular cell adhesion molecule 1 (VCAM-1; INCAM110)], has been identified. VCAM-1 mediates adhesion between endothelial cells and activated lymphocytes and certain tumor cells. Here, using a soluble VCAM-1 fusion protein with receptor globulin (Rg), we examined the role of VCAM-1 in T-cell activation. We observed that CD4+ T cells, which are inefficiently stimulated by immobilized anti-TCR-1 or anti-CD3 monoclonal antibody (mAb) alone, can be induced to proliferate when exposed to immobilized VCAM-1-Rg in conjunction with either immobilized anti-TCR-1 or immobilized anti-CD3 mAb. The costimulatory effects of VCAM-1-Rg on CD4+T cells is inhibited by mAb to either the CD29 (integrin beta 1)-CD49d [very late activation antigen 4 alpha (VLA-4 alpha)] complex on the surface of CD4+ T cells or to VCAM-1. Stimulation of CD4+ T cells with immobilized VCAM-1-Rg and anti-TCR or -CD3 mAb results in the synthesis of both interleukin 2 (IL-2) receptors and IL-2. In addition, anti-CD25 (anti-IL-2 receptor a) mAb significantly inhibited the VCAM-1-Rg/anti-TCR or -CD3 mAb-driven activation of CD4+ T cells, indicating that endogenously produced IL-2 is in part responsible for the observed T-cell proliferation. Collectively, these results suggest that VCAM-1 can play an important costimulatory role during the activation of CD4+ T cells.
authors.affiliation: Oncogen Division, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
mesh_terms: D000911:Antibodies, Monoclonal; D001483:Base Sequence; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D003001:Cloning, Molecular; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D015345:Oligonucleotide Probes; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1