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Selecting and maintaining a diverse T-cell repertoire
Ananda W. Goldrath & Michael J. Bevan
Nature volume 402, pages6–13(1999)Cite this article
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Abstract
To provide a T-cell population that will respond promptly to foreign antigen, the immune system looks inward, using the variety of self-antigens to select and maintain a diverse repertoire of receptors. A protective immune system must include a T-lymphocyte population that is poised to respond to foreign antigenic peptides presented by self-major histocompatibility complex molecules. As the organism cannot predict the precise pathogen-derived antigens that will be encountered, the system uses the diverse array of self-peptides bound to self-major histocompatibility complex molecules, not only to select a receptor repertoire in the thymus, but also to keep nai ¨ve T cells alive and ‘ready for action’ in the periphery.
Main
Originally published as Nature 402, 255–262; 1999
The revelation that T lymphocytes recognize foreign antigen only when presented by major histocompatibility complex (MHC) molecules was made 25 years ago and remains the cornerstone of our understanding of cellular immunity1. The nature of antigen presentation was unknown for more than a decade until it became clear that foreign antigen has to be processed into peptides that can bind stably to the groove of an MHC molecule to allow recognition by the T-cell receptor (TCR)2,3. MHC genes are extremely polymorphic and the various allelic products bind a broad spectrum of different peptides, explaining MHC restriction of T-cell recognition. During T-cell development, immature T cells are chosen to mature on the basis of the ability of their clonally expressed TCR to interact weakly with self-MHC molecules expressed in the thymus. During this process of positive selection, self-peptides bound in the MHC groove are also recognized. Thus, the selection of the TCR repertoire is not based solely on the recognition of one or a few self-MHC structures, but on the recognition of those structures modified by the binding of an enormous diversity of self-peptides. Low-affinity interactions between the newly expressed TCRs and self-peptide–MHC molecules select a diverse repertoire that will be fine-tuned to react strongly to pathogen-derived peptides bound to the same MHC in the periphery. Even after maturing and leaving the thymus, T cells continue to depend on survival signals transmitted by the interaction of the TCR with self-peptide–MHC complexes. The long-term homeostasis of nai ¨ve T cells depends on continuous tickling of the TCR, and the rebound of the size and complexity of the peripheral lymphocyte pool after any marked loss in cell numbers involves recognition of self-peptide–MHC complexes
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