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

J Immunol. 2012 Apr 15;188(8):3920-7. doi: 10.4049/jimmunol.1102587. Epub 2012 Mar 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Apoptosis
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Proliferation
  • Cell Survival
  • Deoxycytidine Kinase / genetics
  • Deoxycytidine Kinase / immunology*
  • Erythrocytes / immunology
  • Erythrocytes / metabolism
  • Ethylnitrosourea / toxicity
  • Gene Silencing
  • Immunity, Innate
  • Immunologic Memory
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Nucleosides / genetics
  • Nucleosides / immunology*
  • Nucleosides / metabolism
  • Sequence Analysis, DNA
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Antigens, CD
  • Nucleosides
  • Deoxycytidine Kinase
  • Ethylnitrosourea