{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:53:40Z","timestamp":1790751220672,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,4,1]],"date-time":"2012-04-01T00:00:00Z","timestamp":1333238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2013induced mutation in the last \u03b1 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 CD44highCD62Llow memory phenotype, with high levels of proliferation and apoptosis. These phenotypes are notably the result of a cell-extrinsic\u2013driven 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1102587","type":"journal-article","created":{"date-parts":[[2012,3,10]],"date-time":"2012-03-10T19:03:05Z","timestamp":1331406185000},"page":"3920-3927","source":"Crossref","is-referenced-by-count":18,"title":["A Deficiency in Nucleoside Salvage Impairs Murine Lymphocyte Development, Homeostasis, and Survival"],"prefix":"10.1093","volume":"188","author":[{"given":"Onjee","family":"Choi","sequence":"first","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean A","family":"Heathcote","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka-Kei","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip J","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazim","family":"Ghani","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric W-F","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip G","family":"Ashton-Rickardt","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Rutschmann","sequence":"additional","affiliation":[{"name":"Section of Immunobiology, Faculty of Medicine, Imperial College London , London W12 0NN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,15]]},"reference":[{"key":"2025032410015253300_r1","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1080\/1042819042000219494","article-title":"Intrinsic and extrinsic regulation of T lymphocyte quiescence","volume":"45","author":"Tzachanis","year":"2004","journal-title":"Leuk. 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Immunol."},{"key":"2025032410015253300_r30","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.1002\/eji.201040577","article-title":"Apoptosis regulators Fas and Bim synergistically control T-lymphocyte homeostatic proliferation","volume":"40","author":"Fortner","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025032410015253300_r31","doi-asserted-by":"crossref","first-page":"4374","DOI":"10.4049\/jimmunol.175.7.4374","article-title":"The death receptor Fas (CD95\/APO-1) mediates the deletion of T lymphocytes undergoing homeostatic proliferation","volume":"175","author":"Fortner","year":"2005","journal-title":"J. Immunol."},{"key":"2025032410015253300_r32","doi-asserted-by":"crossref","first-page":"5014","DOI":"10.4049\/jimmunol.177.8.5014","article-title":"Peripheral T cell lymphopenia and concomitant enrichment in naturally arising regulatory T cells: the case of the pre-Talpha gene-deleted mouse","volume":"177","author":"Bosco","year":"2006","journal-title":"J. Immunol."},{"key":"2025032410015253300_r33","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1172\/JCI200110360","article-title":"Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling","volume":"108","author":"Apasov","year":"2001","journal-title":"J. Clin. Invest."},{"key":"2025032410015253300_r34","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1182\/blood.V90.4.1600","article-title":"Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion","volume":"90","author":"Huang","year":"1997","journal-title":"Blood"},{"key":"2025032410015253300_r35","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.4049\/jimmunol.174.2.1073","article-title":"A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells","volume":"174","author":"Lappas","year":"2005","journal-title":"J. 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