TCR Down-Regulation Controls T Cell Homeostasis

• Published in: The Journal of immunology (1950) Vol. 183; no. 8; pp. 4994 - 5005
• Main Authors: Boding, Lasse, Bonefeld, Charlotte Menne, Nielsen, Bodil L, Lauritsen, Jens Peter H, von Essen, Marina Rode, Hansen, Ann Kathrine, Larsen, Jeppe Madura, Nielsen, Morten Milek, Odum, Niels, Geisler, Carsten
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-10-2009
• Subjects: Animals; Apoptosis - immunology; CD3 Complex - genetics; CD3 Complex - immunology; CD3 Complex - metabolism; Down-Regulation - immunology; Homeostasis - immunology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thymus Gland - immunology; Thymus Gland - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901539

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.