History of the thymus: from an "accident of evolution" to the programming of immunological self-tolerance

Abstract

This synthesis presents the most important disruptions of conceptions about the thymus since its discovery in Antique Greece. For centuries, the thymus was considered as a vestigial organ, and its role in T-lymphocyte differentiation has been proposed only in the 1960's. Most recent studies attribute to the thymus an essential and unique role in the programming of central immunological self-tolerance. The basal mechanism implicated in this function is the transcription in thymic epithelium of genes encoding precursors of self-antigens. Processing of these latter leads to presentation of self-antigens by the major histocompatibility complex (MHC) machinery expressed by thymic epithelial cells and dendritic cells. During fetal life, this presentation drives negative selection of T-cell clones harboring receptors with high affinity for these MHC/self-antigen complexes. After birth, this presentation also promotes the generation of regulatory T cells specific for these complexes. A number of studies, as well as the identification of Aire and Fezf2 genes, have shown that a thymus dysfunction plays a crucial role in the development of organ-specific autoimmunity.