TCR down-regulation controls T cell homeostasis

Lasse Boding, Charlotte Menné Bonefeld, Bodil L Nielsen, Jens Peter Holst Lauritsen, Marina Rode von Essen, Ann Kathrine Hansen, Jeppe Madura Larsen, Morten Milek Nielsen, Niels Odum, Carsten Geisler

Research output: Contribution to journalJournal articleResearchpeer-review

14 Citations (Scopus)

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.
Original languageEnglish
JournalJournal of Immunology
Volume183
Issue number8
Pages (from-to)4994-5005
Number of pages11
ISSN0022-1767
DOIs
Publication statusPublished - 2009

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