TCR down-regulation controls T cell homeostasis

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

Publikation: Bidrag til tidsskriftTidsskriftsartikelForskningpeer review

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.

OriginalsprogEngelsk
TidsskriftJournal of Immunology
Vol/bind183
Udgave nummer8
Sider (fra-til)4994-5005
Antal sider12
ISSN0022-1767
DOI
StatusUdgivet - 15 okt. 2009

Citationsformater

Boding, L., Bonefeld, C. M., Nielsen, B. L., Lauritsen, J. P. H., von Essen, M. R., Hansen, A. K., Larsen, J. M., Nielsen, M. M., Odum, N., & Geisler, C. (2009). TCR down-regulation controls T cell homeostasis. Journal of Immunology, 183(8), 4994-5005. https://doi.org/10.4049/jimmunol.0901539