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A good review of thymic anatomy and the dynamics of T-cell production.
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This is a clear and comprehensive review of positive and negative selection.
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This review of negative selection places many controversial issues into perspective.
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References 7 and 8 describe negative-selection-deficient mice and estimate the fraction of thymocytes that undergo negative selection.
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This paper shows that most thymocytes that undergo apoptosis are located in the medulla.
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References 19–24 describe the promiscuous expression of genes in the thymus. References 19 and 23 show that this promiscuous gene expression originates in thymic epithelial cells.
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This paper decribes autoimmune regulator (Aire)-deficient mice, which lack promiscuous gene expression in the thymus and consequently develop autoimmune polyendocrine syndrome.
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This was the first paper to directly show the deletion of self-reactive thymocytes.
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References 33–35 show that positive and negative selection are not sequential events.
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This paper shows that antagonist peptides mediate positive selection, whereas agonist peptides mediate negative selection. Low doses of agonist peptide did not result in positive selection in this study.
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Reference 39 used surface plasmon resonance to show formally that positive-selecting peptide–MHC ligands have a lower affinity for the T-cell receptor (TCR) than do negative-selecting peptide–MHC ligands.
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This paper clearly shows that perinatal blockade of CD80 and CD86 inhibits negative selection and allows the development of autoreactive T cells. These results are in contrast to those in reference 48, which examines negative selection in CD80 and CD86 double-deficient mice.
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Reference 48 shows that CD40L does not have to be expressed by every thymocyte to induce efficient negative selection; that is, CD40L acts in a non-cell-autonomous manner. This paper also shows that deletion of superantigen-reactive thymocytes occurs in CD80 and CD86 double-deficient animals.
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References 52 and 53 describe the immunological synapse formed by double-positive (DP) thymocytes.
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This paper shows that negative selection is not completely dependent on co-receptor expression.
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This is a recent review on TCR signalling in thymocytes.
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References 64 and 65 describe an autoimmune syndrome that is generated by a point mutation in the linker for activation of T cells (LAT) adaptor.
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This paper shows that mice carrying one functional allele of growth-factor receptor-bound protein 2 (Grb2) are defective in negative but not positive selection.
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Reference 74 shows that a dominant-negative version of NUR77 impairs negative selection, whereas reference 75 shows that negative selection is unimpaired in Nur77-deficient mice. This discrepancy is explained in reference 76, which shows that NOR1 and NUR77 are structurally and functionally redundant.
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This paper shows that negative selection is intact in mice that express a dominant interfering mutant of FAS-associated death domain (FADD). This makes it unlikely that FAS (CD95), tumour-necrosis factor receptor 1 (TNFR1), DR3 or tumour-necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) contribute to negative selection through their death domains.
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Reference 84 shows that Trail−/− mice are defective in negative selection. These results could be contrary to those in reference 83.
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This review puts forward a hypothesis to reconcile the results of references 83 and 84. TRAIL receptors might support thymocyte apoptosis by activating JUN N-terminal kinase (JNK) without using their death domain.
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Reference 92 establishes the importance of BCL-2-interacting mediator of cell death (BIM) in negative selection.
Hildeman, D. A. et al. Activated T cell death in vivo mediated by proapoptotic Bcl-2 family member Bim. Immunity 16, 759–767 (2002).
This paper shows that BIM deficiency compromises the death of activated peripheral T cells.
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