Pseudomonas aeruginosa exotoxin A has been observed to exert modulatory effects on the immune response. The present study examines the ability of exotoxin A to induce proliferation of splenocytes from athymic nu/nu mice. We observed that exotoxin A induced the proliferation of athymic nude splenocytes which could be abrogated by heating the toxin at 70 degrees C or by preincubation of the toxin with rabbit anti-exotoxin A antiserum. Photoaffinity-labelled toxin significantly induced splenocyte proliferation although the relative activity was reduced. Maximum nude splenocyte proliferation was observed at a toxin dose of 100 ng. This same dose was shown previously for athymic splenocytes to induce an enhanced response to the thymus-dependent (TD) antigen, sheep red blood cells (SRBC). The increased [3H]-TdR uptake in athymic splenocytes stimulated by exotoxin A was initiated by 24 hours and continued to day 10. Nude splenocytes depleted of Ig+ and Ia+ cells were induced to proliferate by exotoxin A. Cyclosporin A addition abrogated the ability of exotoxin A to induce proliferation. These results suggest that Pseudomonas aeruginosa exotoxin A can stimulate the proliferation of splenic T lymphocytes in athymic nu/nu mice.