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CD4CD25 SUPPRESSOR T CELLS: MORE QUESTIONS THAN ANSWERS

T cells that were able to suppress immune responses were described first in the early 1970s. Suppressor T cells were thought to be a specialized population, the effects of which were mediated by secreted antigenspecific factors. However, the failure to clone these factors led to the demise of this entire field of study in the early 1980s. Sakaguchi and associates rekindled interest in the concept of T-cell-mediated suppression in the mid-1990s by showing that a minor population (~10%) of CD4 T cells, which co-expresses the interleukin-2 receptor (IL-2R) α-chain (CD25), is crucial for the control of autoreactive T cells in vivo. Subsequent in vitro studies by several groups showed that CD4CD25 T cells are both hyporesponsive and suppressive. CD4CD25 T cells were discovered originally in mice, but a population with identical phenotypic and functional properties has been defined recently in humans. Although the term ‘regulatory T cell’ has replaced the term ‘suppressor T cell’ in the immunology literature, regulatory T cells might both enhance or suppress immune responses.As CD4CD25 T cells only downregulate immune responses, I refer to them here as suppressor T cells. In addition to CD4CD25 T cells — which are best termed ‘naturally occurring suppressor cells’ — several in vitro and in vivo treatments have been shown to generate a spectrum of suppressor T cells (FIG. 1). The oral administration of antigen is the oldest approach used to induce suppressor T cells. The relationship between these induced suppressor T-cell populations and the naturally occurring suppressor populations is unclear. Probably, the most intriguing question that must be addressed is whether any CD4 T cell in the normal peripheral lymphoid environment can develop into a suppressor cell? If so, what are the factors that promote the differentiation of such suppressor cells? Although several reviews have been published recently on suppressor T cells, this is a rapidly evolving area of investigation. Many of the issues that were raised ten years ago about the existence of suppressor T cells are still relevant today (BOX 1). I use a questionand-answer format in this review to address some of these issues and to emphasize important areas of agreement and controversy, as well as directions for future study.