Key Points
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As T cells develop within the thymus, they pass through an ordered sequence of differentiation and proliferation checkpoints to result in the production of mature, correctly selected, non-autoreactive, peripheral T cells.
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Transgenic studies in mice have been fundamental for the genetic dissection of the signal-transduction pathways that occur during T-cell development.
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T-cell-specific promoters, including the human CD2 promoter and the mouse proximal p56lck promoter, have been used to drive T-lineage expression of dominant-negative or gain-of-function mutants of signalling proteins. The heterogeneity and timing of transgene expression can affect the phenotype of transgenic mice and needs to be carefully considered.
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The specificity and mode of action of any putative dominant-negative mutants needs to be investigated prior to the generation of transgenic mice, so various problems in the interpretation of data can be avoided. Similarly, with constitutively active mutants, the localization of the mutant protein must be considered.
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These transgenic approaches need to be used with full awareness of their limitations. The development of new transgenic vectors, which allow for the inducible expression of transgenes, and more detailed biochemical knowledge of signal-transduction pathways will enable further transgenic studies to be performen to increase our understanding of the processes that control thymoctye development.
Abstract
This review examines the value of transgenic studies in mice for the genetic dissection of signal-transduction pathways relevant to thymus development. T-cell development in the thymus is controlled by an ordered sequence of differentiation and proliferation checkpoints that culminate in the production of correctly selected, non-autoreactive, peripheral T lymphocytes. Work in transgenic mice has been fundamental for the preparation of genetic maps of signal-transduction pathways that control T-cell development. This review discusses how tyrosine kinases, guanine-nucleotide-binding proteins and transcription factors converge to control T-cell differentiation and proliferation in the immune system.
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Glossary
- GTPases
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Signalling proteins that bind guanine nucleotides. They are active in the GTP-bound state and are inactivated when they hydrolyse GTP into GDP.
- PRE-T CELLS
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A population of cells found in the thymus that undergo rearrangements of the αβ-subunits of the T-cell antigen receptor complex prior to commitment to the T-cell lineage.
- GTPase-ACTIVATING PROTEIN
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(GAP). A protein that stimulates the intrinsic GTPase activity of small GTPases; for example, for RAS, two GAPs are known, p120 GAP and neurofibromin.
- GUANINE NUCLEOTIDE-EXCHANGE FACTOR
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(GEF). A protein that catalyses guanine nucleotide exchange on GTPases.
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Cantrell, D. Transgenic analysis of thymocyte signal transduction. Nat Rev Immunol 2, 20–27 (2002). https://doi.org/10.1038/nri703
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DOI: https://doi.org/10.1038/nri703
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