A deficiency in nucleoside salvage impairs murine lymphocyte development, homeostasis and survival1

• Published in: The Journal of immunology (1950) 2012-03, Vol.188 (8), p.3920-3927
• Main Authors: Choi, Onjee, Heathcote, Dean A., Ho, Ka-Kei, Müller, Phillip J., Ghani, Hazim, Lam, Eric W.-F., Ashton-Rickardt, Philip G., Rutschmann, Sophie
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102587

The homeostasis of the immune system is tightly controlled by both cell-extrinsic and –intrinsic mechanisms. These regulators, not all known to date, drive cells in and out of quiescence when and where required to allow the immune system to function.Here we describea deficiency in deoxycytidine kinase (DCK), one of the major enzymes of the nucleoside salvage pathway,which affects peripheral T-cell homeostatic proliferation and survival. As a result of an N-ethyl-N-nitrosoUreainduced mutation in the last α-helix of DCK, a functionally null proteinhas been generated in the mouse and affects the composition of the hematopoietic system. Both B- and T-lymphocytes development is impaired, leading to a state of chronic lymphopenia and to a significant increase in the number of myeloid cells and erythrocytes. In the periphery, we found that mutant lymphocytes adopt a CD44 high CD62L low memory phenotype, with high levels of proliferation and apoptosis. These phenotypes are notablythe result of a cell-extrinsic driven lymphopenia-induced proliferation as wild-type cells transferred into DCK-deficient recipients adopt the same profile. In addition, DCK also regulates lymphocyte quiescence in a cell-intrinsic manner. These data establish dCK as a new regulator of hematopoietic integrity and lymphocyte quiescence and survival.