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TCR Down-Regulation Controls T Cell Homeostasis¹

Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

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 CD3 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 CD3LLAA knock-in mice homozygous for a double leucine to alanine mutation in the CD3 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 CD3 mutant mice. The reduced number of naive T cells in CD3 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 CD3LLAA mutation exerted a T cell intrinsic effect on T cell homeostasis that resulted in an increased transition of CD3LLAA naive T cells to memory T cells and a survival advantage of CD3LLAA 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 CD3-mediated TCR down-regulation in T cell homeostasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from The Danish Medical Research Council, The Novo Nordisk Foundation, The A. P. Møller Foundation for the Advancement of Medical Sciences, The Agnes and Poul Friis Foundation, The Director Jacob Madsen & Wife Olga Madsens Foundation, and The Astrid Thaysen Foundation for Basic Medical Sciences.

² Address correspondence and reprint requests to Dr. Carsten Geisler, Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark. E-mail address: cge{at}sund.ku.dk

³ Abbreviations used in this paper: pMHC, peptide MHC; diL, di-leucine based; WT, wild type; PI, propidium iodide; KLF2, Kruppel-like factor 2; S1P₁, sphingosine-1-phosphate receptor 1; BTLA, B and T lymphocyte attenuator.

⁴ The online version of this article contains supplemental material.