Foxp3(+) T Regulatory Cells: Still Many Unanswered Questions—A Perspective After 20 Years of Study

T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3. In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic. The major issue that remains to be resolved is how they mediate their suppressive functions. In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms. Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites. Many of the concepts we have developed are based on in vitro studies, and it remains unclear if these concepts can readily be applied to Treg function in vivo. Our lack of a specific cell surface marker that readily allows us to identify and target Treg in vivo, particularly in man, remains a major stumbling block. Finally, I will review in some detail controversies regarding the origin of Treg, thymus versus periphery, and attempts to reverse Treg suppression by targeting antigens on their cell surface, particularly members of the TNF receptor superfamily. Hopefully, these areas of controversy will be resolved by in depth studies over the next few years and manipulation of Treg function will be placed on a more solid experimental footing.