Effect of Treatments with Cyclosporin A and Anti-Interferon-γ Antibodies on the Mechanisms of Immune Tolerance in Staphylococcal Enterotoxin B Primed Mice

The authors were interested to investigate the effect of Cyclosporin A (CsA), known to block interleukin-2 (IL-2) production, or of anti-interferon-γ antibodies (anti-IFN-γ Abs) in a model of T cell tolerance induced by the injection of the superantigen Staphylococcal Enterotoxin B (SEB) in BALB/c mice. After SEB immunization, tolerance was mainly achieved through deletion and anergy of SEB-reactive Vβ8⁺ T cells. Association of CsA treatment with SEB led to a greater decrease of the percentage of Vβ8⁺ CD4⁺ lymphocytes in the spleen and an abolition of clonal anergy. In contrast, treatment of SEB primed mice with anti-IFN-γ Abs resulted in an increased percentage of Vβ8⁺ CD4⁺ cells without affecting the induction of clonal anergy. The authors found that 1–2 h after SEB priming, splenic mRNA levels of IFN-γ and IL-4 were decreased by either CsA and anti-IFN-γ Abs, whereas FasL, Bcl-2, p. 53, and c-myc levels were not influenced by either treatment. However, SEB-induced IL-2 and IL-10 mRNA expression was suppressed only by CsA, whereas tumour necrosis factor-α (TNF-α) was decreased only by anti-IFN-γ Abs. To investigate whether the effect of CsA on the tolerance mechanisms was related to suppression of IL-2, CsA was administered together with recombinant IL-2. Whereas anergy was not influenced, the decreased percentage of Vβ8⁺ CD4⁺ cells seen in CsA-treated animals in the second week after SEB injection was partially corrected by the administration of IL-2. Experiments involving bromodeoxiuridine incorporation revealed that the latter effect of IL-2 was mainly due to a correction of the defective proliferation of Vβ8⁺ T cells after SEB injection in CsA-treated mice. These results suggest that the effect of CsA and anti-IFN-γ Abs on tolerance mechanisms are in part explained by their action on cytokines.