Negative selection — clearing out the bad apples from the T-cell repertoire

CD4+CD8+ double-positive (DP) thymocytes undergo one of three fates in the thymus: positive selection, negative selection or death by neglect. Negative selection of thymocytes that express T-cell receptors (TCRs) with high affinity for self-peptide–MHC (∼5% of the total) deletes potentially self-reactive thymocytes, generating a largely self-tolerant peripheral T-cell repertoire. Most negative selection is thought to occur in the thymic medulla as this contains two types of specialized antigen-presenting cell — dendritic cells and thymic epithelial cells (TECs). Medullary TECs transcribe genes that are normally expressed in peripheral tissues. Negative selection can occur before or after positive selection and in thymocytes at all stages of development. So, positive and negative selection are probably independent, and not sequential, events. Negative selection in response to high-affinity ligands might be due to increased TCR occupancy or a slower 'off-rate' (kinetic proofreading). A second co-stimulatory signal, in addition to the TCR signal, might be required for negative selection. However, there are discrepancies between blocking experiments and genetically deficient mice in this regard. The kinetics of mitogen-activated protein kinase (MAPK) signalling are thought to determine positive- versus negative-selection signals. Extracellular signal-regulated kinase (ERK) is induced more rapidly during negative selection, which might determine the particular transcription factors (such as NUR77 and NF-κB) that are triggered. Linker for activation of T cells (LAT) and phosphatase and tensin homologue (PTEN) are also thought to be involved in negative selection. Death-domain-containing proteins, such as CD95 (FAS) and tumour-necrosis factor receptors (TNFRs), that are involved in the apoptosis of peripheral T cells are not thought to be important for negative selection. Rather, negative selection might occur independently of death domain signalling.