Shimon Sakaguchi
Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Naturally Arising CD25+CD4+ Regulatory T Cells in Auto-Immunity and Tumor Immunity

There is accumulating evidence that naturally arising CD4+regulatory T cells (T-reg), the majority of which constitutively express CD25, actively contribute to the maintenance of natural immunologic self-tolerance. Removal of CD25+CD4+T-reg from the periphery of normal mice, for example, leads to spontaneous development of various autoimmune diseases. CD25+CD4+T-reg also constitutively express CTLA-4 and GITR (glucocorticoid-induced TNF receptor-related gene); and blockade of CTLA-4 or ligation of GITR on the T-reg by specific monoclonal antibodies (mAb) can attenuate their suppressive activity, leading to the development of autoimmune disease.

As the other side of the coin, naturally present CD25+CD4+T-reg may impede development of tumor immunity by hampering the generation and activation of tumor-effector T cells recognizing autologous tumor cells. Indeed, reduction of CD25+CD4+T-reg by administration of anti-CD25 mAb for a limited period provoked effective tumor-specific immunity against syngeneic tumor cells. Furthermore, administration of anti-CTLA-4 or anti-GITR mAb resulted in enhanced tumor immunity partly due to attenuation of the suppressive activity of natural CD25+CD4+T-reg and consequent activation of tumor effector cells. Tumor effector cells can also be generated in vitro by simply eliminating CD25+CD4+T cells from splenic cell suspensions prepared even from tumor-nonsensitized mice. In this in vitro induction of tumor immunity, CD25-CD4+T cells responding to self-peptides/class II MHC molecules expressed on syngeneic APCs spontaneously proliferated upon removal of CD25+CD4+regulatory T cells. A large amount of IL-2 produced by such CD4+self-reactive T cells generated NK-like tumor effector cells as lymphokine-activated killer (LAK) cells capable of promiscuously killing various tumor cells.

Thus, removal or functional alteration of CD25+CD4+T-reg can abrogate immunological unresponsiveness to syngeneic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans.