Tolerance to Self: Which Cells Kill

Primer T he mammalian immune system is tightly controlled to be activated by infectious agents but not by self. The ability to respond to the universe of potential antigens is mediated by a repertoire of T and B lymphocytes with an extraordinary range of specificities. The diversity of T and B lymphocyte antigen receptors is generated by completely random rearrangement of gene segments. Thus, this diverse repertoire must be purged of autoreactive specificities—a process known as negative selection. T cell tolerance is established in the thymus, an organ uniquely specialized to support the development of T cells and regulate their self-tolerance. In a recent paper published in PLoS Biology [1], Ahn and colleagues delve into a longstanding question about the process of negative selection: which cells in the thymus induce tolerance to self to prevent autoimmunity? The developmental fate of thymocytes, T cell precursors, is regulated by signals delivered to the T cell receptor (expressed on the thymocyte) by peptide/major histocompatibility complex (MHC) molecules expressed on thymic stromal cells. Developing thymocytes interact with peptide/MHC molecules expressed by both thymic epithelial cells and bone marrow–derived dendritic cells (DCs). The thymus is divided into two distinct regions: an outer cortex and an inner medulla. Thymic epithelial cells are present in both regions; DCs primarily localize to the medulla and the corticomedullary junction. Cortical and medullary epithelial cells arise from a single precursor but are phenotypically and functionally quite distinct, and, as shown by the current authors and others, exist as heterogeneous populations. T cell development occurs in specialized thymic microenvironments established by the stromal cells. For many of these processes, the localization of the event and the thymic cell mediating that process are quite clear. T cell precursors enter the thymus at the corticomedullary junction and rearrange T cell receptor (TCR) genes in the cortex. Immature thymocytes in the cortex integrate primary signals transduced by the TCR with secondary, costimulatory signals. If an inadequate signal is received, the cell commits suicide: death by neglect. Positive selection is the crucial step in which thymocytes that can interact productively with self-peptide/ MHC molecules survive and differentiate further. Immature thymocytes screened for positive selection localize to the outer cortex, and it is well accepted that cortical epithelium is uniquely capable of directing the positive selection of traditional αβ-expressing T cells. The process of rescuing cells that can interact with self-peptide/MHC complexes enriches for autoreactive T …