Epstein-Barr virus immunosuppression: II. Generation of nonspecific suppressor T lymphocytes in vitro

We have previously shown that antigen-specific T-suppressor (Ts) cells can be generated in vitro by antigens of Epstein-Barr virus (EBV). However, patients with EBV-associated disorders and particularly those with EBV-induced infectious mononucleosis characteristically have nonspecific Ts cells in their peripheral circulation. To explore this apparent paradox, we have now examined the interaction of EBV antigens with either an unrelated antigen (tuberculoprotein—PPD) or a T-cell mitogen (phytohemagglutinin—PHA) in the in vitro generation of Ts cells. Our findings are: (1) the presence of unrelated antigens results in the generation of nonspecific Ts cells in a system wherein an EBV antigen (in excess) alone otherwise induces only antigen-specific Ts cells; (2) the unrelated antigen may be present in a wide range of concentrations and (3) can contribute to nonspecific Ts cell generation when added as long as 2 days after initiation of induction by EBV antigen; (4) the unrelated antigen must be recognized by the sensitized lymphocytes in order for nonspecific Ts cells to be induced; and most interestingly (5) when a second, immunologically different, EBV antigen is substituted for the unrelated antigen (PPD), again nonspecific Ts cells are induced in this system. We propose that the presence of unrelated (or multiple) antigens, in addition to the antigen-specific Ts cell-inducing antigen, contributes to the generation of nonspecific Ts cells in vivo, and that this phenomenon may be important in infections, malignancies, and immunodeficiency states.