The discovery of regulatory T cells: a paradigm shift in immunology

The immune system is conventionally viewed as an army of fighters present naturally in an inactive state, ready to react to microbial invasion. Activation follows the detection of microbial molecules either by innate receptors, which are broadly expressed across cell types, or by antigen-specific receptors - the T cell receptor (TCR) and B cell receptor (BCR) - exclusively found on T and B lymphocytes, respectively. Previously to the discovery of regulatory T cells (Tregs), the induction of immune responses was thought to be controlled exclusively by the provision of activation signals coming from "outside" of the immune system. The discovery of regulatory T cells (Tregs) revealed a radically different mode of immune control. It emphasized immune activation as the default phenomenon at steady state, underlining suppression as essential to maintain immune homeostasis. Under this new view, the induction of immune response can proceed without external signal, upon the removal of key immune breaks internal to the immune system and embodied by Tregs. It fundamentally transformed our understanding of immune regulation and opened new therapeutic avenues for diseases ranging from autoimmunity to cancer. The immense impact of this work was rewarded this year by the attribution of the Nobel prize of Physiology and Medicine to Prof. Shimon Sakaguchi, Prof. Mary E. Brunkow, and Prof. Fred Ramsdell. In this article, we outline the scientific context of these discoveries in the 1990s, and discuss their impact for our understanding of the immune system and the development of novel therapies.