Interest in regulatory T cells has exploded since the discovery by Sakaguchi and colleagues of a minor population of CD4+ CD25+ T cells which plays a central role in the prevention of autoimmune reactions in vivo. 'Natural regulatory T cells' develop in the thymus, are present in naïve animals and their depletion causes the development of a spectrum of autoimmune. By contrast, 'adaptive or induced' regulatory T cells develop in peripheral lymphoid tissues. TGF-; and IL-10 may be involved in the conversion of CD4+ CD25- T cells into CD4+ CD25+ FoxP3+ which display suppressive activity. Our laboratory has undertaken studies to evaluate the role of natural regulatory T cells in the control of humoral and cellular responses. Our results show elimination of natural regulatory T cells (which constitutively express CD25) led to increased antigen-specific antibody production but did not affect T-independent B cell responses, suggesting that CD4+ CD25+ T exert a feedback mechanism on antibody secretion by selectively dampening the T cell help for B cell activation. Similarly, natural regulatory T cells downregulate activation of Th1 (but not Th2) 'type responses, as demonstrated by a strong increase in IFN production and CTL activity in mice immunized with antigen-pulsed DCs and depleted of CD25+ cells (see above discussion). Although active suppression mediated by the naturally occurring CD4+ CD25+ regulatory T cells is crucial for peripheral tolerance and prevention of autoimmunity, it might also, in some circumstances, be considered as an obstacle to successful vaccination, in particular in cancer patients (see below). In the course of studies aimed at evaluating the function in vivo of the inhibitory receptor CTLA-A4, we found that treatment of mice with anti-CTLA4 mAb (4F10, kindly provided by J. Bluestone) at the time of priming induced the development of a population of ICOShi CD4+ T cells producing IL-10 and expressing FoxP3. These induced regulatory T cells seem to be distinct from the naturally occurring Treg and inhibit primary and memory Th1 responses. Experiments are under way to test the role of IL-10 and the enzyme indoleamine 2, 3 dioxygenase in the CTLA-4-induced down-regulation of Th1-type responses.