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The Th1/Th2 concept brought an attractive explanation of the active self tolerance which appears to control the onset of pathogenic autoimmunity. New data coming from various independent horizons indicate that self immunoregulation could also depend to a large extent on non-Th2 cells. Original data derived from the day-3-thymectomy model, selective T-cell lymphocytopenia and nonobese diabetic mice are discussed in an effort to analyze similarities and differences in phenotype (CD25, CD62L and CD45RB) and cytokine pattern (notably interleukin (IL)-4, IL-10 and transforming growth factor (TGF)β) of regulatory cells involved in these models. The relationship of these cells with Th3, Tr1 and natural killer (NK) T cells are also discussed. The hypothesis is proposed that CD25 CD62L T cells mediate the physiologic regulation of self regulation whereas Th2 and Th3 cells are essentially induced following sensitization against autoantigens.