NDLI: TCR down-regulation controls T cell homeostasis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Bonefeld, Charlotte Menné Odum, Niels Hansen, Ann Kathrine Lauritsen, Jens Peter H. Nielsen, Bodil L. Von Essen, Marina Rode Larsen, Jeppe Madura Boding, Lasse Nielsen, Morten Milek Geisler, Carsten
Description	Country affiliation: Denmark Author Affiliation: Boding L ( Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.)
Abstract	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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	8
Volume Number	183
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2009-10-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Antigens, Cd3 Immunology Homeostasis Receptors, Antigen, T-cell T-lymphocytes Thymus Gland Animals Genetics Metabolism Apoptosis Down-regulation Mice Mice, Inbred C57bl Mice, Mutant Strains Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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