CTLA-4 (CD152) inhibits the specific lysis mediated by human cytolytic T lymphocytes in a clonally distributed fashion

Since the functional outcome of effector T lymphocytes depends on a balance between activatory and inhibitory receptors, we studied the ability of CTL A-4 (CD152) to inhibit the cytolytic function of CTL. In 22 TCR alpha beta( +)CD3(+)8(+) CTL clones, activation induced by anti-CD3, anti-CD28, or anti -CD2 mAb was inhibited by anti-CD152 mAb in a redirected killing assay. In eight clones inhibition was >40%, in 10 it ranged between 20-40%, and in fo ur it was <20%. This suggests the existence of a clonal heterogeneity as we ll as for the ability of CTLA-4 to inhibit CD3/TCR-, CD28-, or CD2-mediated CTL activation. To support further this contention, we used an experimenta l model based upon Ag-specific CTL, Eight Ag-specific T cell clones that ly se autologous EBV-infected B lymphocytes, but are unable to lyse allogeneic EBV-infected B cell lines, were used in a cytolytic assay in which anti-CD 152 mAb or soluble recombinant receptor (i.e., CTLA-4 Ig) were included. In this system, at variance from the redirected killing assay, cross-linking of surface molecules by mAb does not occur. Thus, addition of anti-CD152 mA b or of CTLA-4 Ig and anti-CD80/CD86 mAb to the assay should result in a bl ockade of receptor/ligand interactions. As a consequence, inhibition of a n egative signal, such as that delivered via CD152, should enhance lysis, A > 40% increment of target cell lysis was achieved in three of eight clones st udied. Since it is not equally shared by all CTL clones, this feature also appears to be clonally distributed.