title: A deficiency in nucleoside salvage impairs murine lymphocyte development, homeostasis, and survival.
abstract: 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. In this article, we describe a 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-nitrosourea-induced mutation in the last α helix of DCK, a functionally null protein has been generated in the mouse and affects the composition of the hematopoietic system. Both B and T lymphocyte 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 notably the 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.
authors.affiliation: Section of Immunobiology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Onjee
authors.initials: O
authors.lastname: Choi
authors.forename: Dean A
authors.initials: DA
authors.lastname: Heathcote
authors.forename: Ka-Kei
authors.initials: KK
authors.lastname: Ho
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Müller
authors.forename: Hazim
authors.initials: H
authors.lastname: Ghani
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Philip G
authors.initials: PG
authors.lastname: Ashton-Rickardt
authors.forename: Sophie
authors.initials: S
authors.lastname: Rutschmann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism; D005038:Ethylnitrosourea / Q000633:toxicity; D020868:Gene Silencing; D007113:Immunity, Innate; D007156:Immunologic Memory; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009705:Nucleosides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D009705:Nucleosides; D003842:Deoxycytidine Kinase; D005038:Ethylnitrosourea