| TCR down-regulation controls T cell homeostasis. | |
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MedLine Citation:
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PMID: 19801521 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TCR and cytokine receptor signaling play key roles in the complex homeostatic mechanisms that maintain a relative stable number of T cells throughout life. Despite the homeostatic mechanisms, a slow decline in naive T cells is typically observed with age. The CD3gamma di-leucine-based motif controls TCR down-regulation and plays a central role in fine-tuning TCR expression and signaling in T cells. In this study, we show that the age-associated decline of naive T cells is strongly accelerated in CD3gammaLLAA knock-in mice homozygous for a double leucine to alanine mutation in the CD3gamma di-leucine-based motif, whereas the number of memory T cells is unaffected by the mutation. This results in premature T cell population senescence with a severe dominance of memory T cells and very few naive T cells in middle-aged to old CD3gamma mutant mice. The reduced number of naive T cells in CD3gamma mutant mice was caused by the combination of reduced thymic output, decreased T cell apoptosis, and increased transition of naive T cells to memory T cells. Experiments with bone marrow chimeric mice confirmed that the CD3gammaLLAA mutation exerted a T cell intrinsic effect on T cell homeostasis that resulted in an increased transition of CD3gammaLLAA naive T cells to memory T cells and a survival advantage of CD3gammaLLAA T cells compared with wild-type T cells. The experimental observations were further supported by mathematical modeling of T cell homeostasis. Our study thus identifies an important role of CD3gamma-mediated TCR down-regulation in T cell homeostasis. |
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Authors:
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Lasse Boding; Charlotte Menné Bonefeld; Bodil L Nielsen; Jens Peter H Lauritsen; Marina Rode von Essen; Ann Kathrine Hansen; Jeppe Madura Larsen; Morten Milek Nielsen; Niels Odum; Carsten Geisler |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 183 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-10-05 Completed Date: 2009-11-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 4994-5005 Citation Subset: AIM; IM |
Affiliation:
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Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD3 / genetics, immunology*, metabolism Apoptosis / immunology Down-Regulation / immunology Homeostasis / immunology* Mice Mice, Inbred C57BL Mice, Mutant Strains Receptors, Antigen, T-Cell / immunology*, metabolism T-Lymphocytes / immunology*, metabolism Thymus Gland / immunology*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD3; 0/CD3 antigen, gamma chain; 0/Receptors, Antigen, T-Cell |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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