We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV -specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV -specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence.

Antigen-specific human T cell clones specific for defined peptides of influenza A hemagglutinin were found to be rendered unresponsive by incubation with moderately high concentrations of antigen. This was the case whether the synthetic peptide antigen was present for the duration of the culture or the cloned T cells were preincubated with antigen for 3-18 h at 37 degrees C, before stimulation with T-depleted irradiated sheep erythrocyte non-rosette-forming lymphocytes (E-) pulsed with the optimal dose of peptide. Tolerance could not be overcome by culture with various numbers of E- cells and antigen. The induction of unresponsiveness was antigen specific, since it depended upon incubation with the appropriate peptide recognized by that clone. In addition, the tolerant T cells remained unresponsive to stimulation with the specific peptide for at least 7 d after induction even though maintained in culture in the presence of T cell growth factor. This state of antigen-specific unresponsiveness is akin to immunological tolerance. Furthermore, the experiments reported here demonstrate that the helper T cell clone can be inhibited by the relevant peptide in the absence of any suppressor cells or their precursors. This suggests that antigen-induced unresponsiveness need not always depend on the presence of suppressor T cells. The induction of tolerance in T cell clones does not result in early T cell death, since cells that no longer proliferate in response to the specific antigen and accessory cells still proliferate in response to T cell growth factor.

Both thymus and bone marrow cells of adult mice can be made specifically unresponsive to human gamma globulin, but each cell population displays a distinct kinetic pattern for both the induction and spontaneous loss of the unresponsive state. These kinetics appear to be much slower in the bone marrow cells than in the thymus cells. In addition, the dose of deaggregated human gamma globulin needed to induce unresponsiveness in bone marrow cells is much greater than that needed to induce unresponsiveness in thymus cells. Apparently, unresponsiveness in only one cell type is sufficient for the tolerant state to be exhibited by the intact animal.

Bacterial lipopolysaccharide (LPS) I has among its broad spectrum of immunologic activities the capacity to modulate the induction of a specific state of tolerance in mice to the thymus-dependent antigen human IgG (HGG), into a specific state of immunity to HGG (1). Mice treated with LPS shortly after the injection of a tolerogenic dose of deaggregated HGG (DHGG) not only fail to become tolerant to HGG (2), but demonstrate a delayed primary response to HGG, and also respond anamnestically to a subsequent immunogenic challenge of aggregated HGG (AHGG) (1). This phenomenon, which has been viewed as a very stringent test of an adjuvant effect (3), was originally described by Claman (4) with bovine gamma globulin tolerance in mice, and has also been seen more recently by Ornellas et al. (5) with sheep gamma globulin tolerance in rats.Recent studies have been directed toward precisely defining the cellular basis of this modulatory effect of LPS on HGG tolerance. It was found that the ' immune response to HGG which is seen as the result of dual treatment of mice with DHGG and LPS appears to occur in spite of the normal induction of tolerance in both HGG-specific thymocytes (1) and peripheral T cells (6). These observations suggest that LPS not only prevents tolerance induction in B cells, but also overcomes the normal requirement for HGG-specific T-helper cells. Furthermore, a positive correlation exists between the capacity of LPS to * This is Publication no.