“In this review, we postulate that the primary inhibition of T cell activation is strictly cell-to-cell contact-dependent and mediated by naturally occurring CD25+ Tregs.”

The discovery that tolerance to self is in large part controlled by a specialized population of regulatory T cells (Tregs) partially controlled by dendritic cells (DC) has revolutionized our concepts in tumor immunology, autoimmunity, transplantation tolerance, and infectious diseases. Furthermore, it likewise challenges the validity of current immunotherapeutic approaches to many of these immunological diseases. We hope that this brief review gives an objective overview in the field of Treg research and points to innovative concepts for the curative treatment of dysregulated immune responses.

Since there are apparently conflicting results in the literature, we try to explain the controversial data by our recent findings. Whereas most investigators have found that the suppressive properties of CD25+ Tregs in vitro are strictly cell contact-dependent and independent of soluble agents, studies in mice suggest that IL-10 and TGF-β are important for their systemic suppressing effects in vivo. In this review, we postulate that the primary inhibition of T-cell activation is strictly cell-to-cell contact-dependent and mediated by naturally occurring CD25+ Tregs. This mechanism leads to a limited local suppression. Additionally, CD25+ Tregs confer suppressive activities to the coactivated T cells and convert them into secondary suppressor T cells, which produce immunosuppressive cytokines, responsible for systemic inhibition of T cell responses. These findings can explain the controversial data in the literature.

CD25+ Tregs are a specialized CD4+ T cell population. Controlling the activation of autoaggressive CD4+ and CD8+ T cells prevents autoimmunity. At the same time, they also diminish the immunological defense of tumor cells. On the one hand, CD25+ Tregs suppress the activation of conventional T cells while, on the other hand, they also convey suppressive activity to the conventional T cells and thereby induce secondary suppressor T cells. The activity and induction of regulatory T cells can be controlled by dendritic cells.

I had started with the characterization of human DC as natural adjuvants for immunotherapy of cancer. However, in 1999 we found that the T cell stimulatory capacity of DC is strictly dependent on their state of maturation and activation and have shown that immature DC are able to induce anergic T cells with strong suppressive activities (Jonuleit et al., "Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells," J. Exp. Med.192:1213-1222, 2000). Therefore, we changed our focus to the characterization of human regulatory T cells (Jonuleit et al., "Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood," J. Exp. Med. 193:1285-1294, 2001 and Jonuleit et al., "Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4+ T helper cells," J. Exp. Med. 196:255-260, 2002).