title: Costimulation with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 augments activation-induced death of antigen-specific CD4+ T lymphocytes.
abstract: Integrin ligands intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) can efficiently costimulate proliferation of resting T cells but not that of Ag-specific T cells. In contrast, CD28 ligand B7 and CD2 ligand leukocyte function-associated Ag (LFA-3) can support IL-2 synthesis and proliferation of Ag-specific T cells more efficiently than that of resting T cells. The molecular basis for this differential costimulation of T cells is poorly understood. In this study, using mAb and soluble IgC gamma 1 chimeras of these adhesion molecules, we demonstrate that coligation of the TCR and CD11a/CD18 (LFA-1/beta 2 integrin) or CD29/CD49d (very late activation Ag-4/beta 1 integrin) using anti-TCR mAb and either ICAM-1 or VCAM-1 induces activation-dependent death of DRw6-specific CD4+ T cells. Similar coligation of the TCR with CD2 or CD28 using either mAb or ligands LFA-3 or B7 not only lacked the ability to induce death but also failed to reverse or inhibit integrin-facilitated death of DRw6-specific T cells. Each of these ligands augmented anti-TCR mAb-induced transcription of IL-2 and IL-4 genes. Exogenous addition of IL-2 and IL-4 did not reverse the integrin-supported T cell death. The death-promoting costimulatory effects of ICAM-1 and VCAM-1 were observed with Ag-specific chronically stimulated T cells but not with either resting T cells or those activated in short-term cultures. Treatment of T cells with cyclosporin A or a protein tyrosine kinase inhibitor herbimycin A inhibited ICAM-1 or VCAM-1-promoted activation-induced T cell death. The Ag-specific T cells that survived death-promoting effects of ICAM-1 or VCAM-1 proliferated efficiently upon restimulation with these ligands. Exposure of DRw6-specific T cells to DRw6+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC but not DR3+ B7+ ICAM-1+ LFA-3+ VCAM-1+ APC induced death of these T cells. This effect was blocked by pretreatment of T cells with mAb directed at CD18 or CD29 but not with those against CD2 or CD28. Taken together, these results suggest that TCR-directed engagement of integrins by their ligands ICAM-1 or VCAM-1 induces activation-dependent death of some perhaps more differentiated Ag-specific T cells and this may be an important homeostatic mechanism by which functional expression of Ag-specific T cells is regulated during an ongoing immune response.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: K
authors.initials: K
authors.lastname: Klussman
authors.forename: G
authors.initials: G
authors.lastname: Leytze
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
mesh_terms: D000938:Antigen-Presenting Cells / Q000502:physiology; D001483:Base Sequence; D016227:Benzoquinones; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007378:Interleukins / Q000502:physiology; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011809:Quinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D016227:Benzoquinones; D015815:Cell Adhesion Molecules; D007378:Interleukins; D047029:Lactams, Macrocyclic; D011809:Quinones; D011948:Receptors, Antigen, T-Cell; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D017828:Rifabutin; C020754:herbimycin; D016572:Cyclosporine