Selective induction of immunological tolerance in antiviral T killer cells of inbred mice after treatment with cyclosporin A

Abstract

Primary anti-influenza A cytotoxic thymus-derived (T) and bone marrow (B) lymphocyte-dependent responses in inbred mice were used as an in vivo model system to study the effects of the immunosuppressive fungus metabolite cyclosporin A (CyA). Five consecutive daily oral applications of CyA, with the first being given 1 or 2 h before virus inoculation of the animals, caused a complete blockage of induction of anti-influenza T killer cells and a partial reduction of cytotoxic B lymphocyte activities. Adoptive cell transfer experiments revealed that incapability to respond was due neither to humoral factors nor to the generation of suppressor cells. The tolerance state appeared to be specific for influenza A; cytotoxic T lymphocytes against allogeneic cell surface determinants could be stimulated in immunosuppressed mice. CyA treatment abolished virus-specific and cross-reactive anti-influenza killer T cell responses. Suppression was of short duration: less than 1 week for B cell-dependent functions, and between 1 and 2 weeks for T killer cell responses. Animals appeared to be normal with regard to both of these cellular activities for 4 weeks after tolerance induction. Thus, the data indicate that CyA exerted preferential effects on killer T cells. Moreover, evidence was presented that CyA treatment during an ongoing influenza infection did not increase sensitivity to that virus. Mice with no measurable cytolytic anti-influenza T killer cell activities but significant B cell responses, although partially diminished by the drug, were completely protected against the lethal effects of influenza infection.