Chronic exposure to superantigen induces regulatory CD4(+) T cells with IL-10-mediated suppressive activity.
The repeated injection of bacterial superantigens (SAg), such as staphylococcus enterotoxin (SE) A or B, has been shown in mice to induce a state of unresponsiveness characterized by the lack of secretion of Th1 lymphokines, such as IL-2 and IFN-gamma, following subsequent SAg challenge. We made the observation, in vivo as well as in vitro, that unresponsiveness to SAg could be transferred from SEA- to SEB-reactive T cells (and reversibly from SEB- to SEA-specific T cells) in C57BL/6 mice but not in BALB/c mice. Since C57BL/6 mice, unlike BALB/c mice, possess TCR V(beta)3+ and V(beta)11+ T cells able to react with both SEA and SEB, we hypothesized that SAg-unresponsive V(beta)3(+) and V(beta)11+ T cells could mediate linked suppression of other SAg-reactive T cells. To analyze further this possibility, spleen cells from BALB/c mice made unresponsive to SEB were tested for their capacity to suppress the response of normal BALB/c cells to SEB. The production of both IFN-gamma and IL-2 following SEB stimulation was greatly impaired in co-cultures containing CD4(+) T cells, but not CD8(+) T cells, isolated from unresponsive animals. In vivo, the production of both IFN-gamma and IL-2 responses to SEB was dramatically reduced in animals adoptively transferred with unresponsive spleen cells. This suppression was abrogated in recipients injected with neutralizing anti-IL-10 antibodies. Moreover, in animals made unresponsive to SEB, SAg-reactive CD4(+) T cells were found to express high levels of CTLA-4, a molecule recently described to play an essential role in the suppressive function of regulatory T cells. Taken together these results demonstrate that the repetitive injection of SAg induces the differentiation of regulatory CD4(+) T cells capable of suppressing SAg-reactive naive T cells.
Laboratory of Experimental Immunology, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
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Noël
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Florquin
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Goldman
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Braun
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D004731:Endotoxins / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000032:analysis; D007371:Interferon-gamma / Q000032:analysis / Q000097:blood; D016753:Interleukin-10 / Q000276:immunology*; D007376:Interleukin-2 / Q000032:analysis / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013210:Staphylococcus / Q000276:immunology*; D013491:Suppressor Factors, Immunologic
D000906:Antibodies; D000942:Antigens, Bacterial; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004731:Endotoxins; D004768:Enterotoxins; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D013491:Suppressor Factors, Immunologic; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D000069594:Abatacept; D007371:Interferon-gamma