Impairment of the cellular immune response in acute murine toxoplasmosis: regulation of interleukin 2 production and macrophage-mediated inhibitory effects.
Depression of the cellular immune response to Toxoplasma gondii has been reported in both mice and humans. The present study was undertaken to determine the kinetics and mechanism of the observed downregulation of interleukin 2 (IL-2) production during experimental murine toxoplasmosis. For these investigations, the cell-mediated immune response to the wild type (PTg) was compared with that to the less-virulent mutant parasite (PTgB), which is deficient in the major surface antigen, p30 (SAG-1). Spleen cells from infected A/J mice failed to proliferate in response to Toxoplasma antigens during the first week of infection. Both PTg- and PTgB-infected A/J mice exhibited a significant reduction in the concanavalin A (Con A)-induced lymphoproliferative response. Further, the response of splenocytes from mice infected with the wild-type parasite was significantly diminished compared with that of mice infected with PTgB. The lymphoproliferative response to Con A reached its nadir at day 7 and remained below control levels for at least 14 days postinfection. By day 21 postinfection, the response to Con A and to Toxoplasma antigens was restored to the level observed prior to day 7. Con A-stimulated culture supernatants of spleen cells from mice on day 7 postinfection contained significantly less IL-2 than normal mice. There was no significant difference in the numbers of binding sites or capacity of high-affinity IL-2 receptors between infected and normal mouse splenocytes as determined by Scatchard analysis. Exogenous IL-2 at different concentrations failed to restore the proliferative response of lymphocytes from infected mice to Con A. Adherent macrophages from 7-day-infected mice were able to suppress IL-2 production by normal splenocytes following stimulation with Con A. The inhibitory activity mediated by infected cells was reversed by the antibody to IL-10 but not transforming growth factor beta. There were insignificant levels of nitric oxide production in both infected and normal splenocytes. These results indicate that during acute murine toxoplasmosis, there is a well-defined period (day 7) during which both the T-cell mitogen and parasite antigen-associated lymphoproliferative response are reduced. Further, there is a reduction in the production of IL-2 and an increase in IL-10, which appear to mediate, in part, the observed downregulation of immunity to T. gondii.
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Department of Medicine and Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03755.
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Kasper
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D000208:Acute Disease; D000818:Animals; D000953:Antigens, Protozoan; D003208:Concanavalin A / Q000494:pharmacology; D015536:Down-Regulation; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000953:Antigens, Protozoan; D007376:Interleukin-2; D015800:Protozoan Proteins; D015375:Receptors, Interleukin-2; C047168:SAG1 antigen, Toxoplasma; D016212:Transforming Growth Factor beta; D003208:Concanavalin A; D016753:Interleukin-10; D009569:Nitric Oxide