COSTIMULATION WITH INTEGRIN LIGANDS INTERCELLULAR-ADHESION MOLECULE-1OR VASCULAR CELL-ADHESION MOLECULE-1 AUGMENTS ACTIVATION-INDUCED DEATH OF ANTIGEN-SPECIFIC CD4-LYMPHOCYTES( T)

Integrin ligands intercellular adhesion molecule-1 (ICAM-1) and vascul ar cell adhesion molecule-1 (VCAM-1) can efficiently costimulate proli feration of resting T cells but not that of Ag-specific T cells. In co ntrast, 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 ba sis for this differential costimulation of T cells is poorly understoo d. In this study, using mAb and soluble IgCgamma1 chimeras of these ad hesion molecules, we demonstrate that coligation of the TCR and CD11a/ CD18 (LFA-1/beta2 integrin) or CD29/CD49d (very late activation Ag-4/b eta1 integrin) using anti-TCR mAb and either ICAM-1 or VCAM-1 induces activation-dependent death of DRw6-specific CD4+ T cells. Similar coli gation of the TCR with CD2 or CD28 using either mAb or ligands LFA-3 o r B7 not only lacked the ability to induce death but also failed to re verse 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 rever se the integrin-supported T cell death. The death-promoting costimulat ory effects of ICAM-1 and VCAM-1 were observed with Ag-specific chroni cally stimulated T cells but not with either resting T cells or those activated in short-term cultures. Treatment of T cells with cyclospori n A or a protein tyrosine kinase inhibitor herbimycin A inhibited ICAM -1 or VCAM-1 -promoted activation-induced T cell death. The Ag-specifi c T cells that survived death-promoting effects of ICAM-1 or VCAM-1 pr oliferated 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 togethe r, these results suggest that TCR-directed engagement of integrins by their ligands ICAM-1 or VCAM-1 induces activation-dependent death of s ome 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.