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CD4⁺CD25⁺ and CD4⁺CD25^- T Cells Act Respectively as Inducer and Effector T Suppressor Cells in Superantigen-Induced Tolerance¹

Pascal Feunou^*, Lionel Poulin^*, Claude Habran^*, Alain Le Moine^*, Michel Goldman^* and Michel Y. Braun^2,*,

^* Laboratory of Experimental Immunology, Université Libre de Bruxelles, Brussels, Belgium; and Laboratory of Immunology, University of Lille 2, Pôle Recherche, Lille, France

The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4⁺ TCRBV8⁺ T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN- secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4⁺ T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4⁺CD25⁺ splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4⁺CD25^- T regulatory cells prevented SEB-induced death independently of CD4⁺CD25⁺ T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25⁺ cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4⁺CD25⁺ T regulatory cells are required for the induction of SAg-induced tolerance, CD4⁺CD25^- T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.

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