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Proliferating cells including activated lymphocytes require deoxyribonucleoside triphosphates (dNTPs) for DNA replication. dNTPs can be synthesised via the de novo pathway from precursors such as glucose and amino acids or the deoxyribonucleoside salvage pathway from extracellular deoxyribonucleosides. Deoxycytidine kinase (dCK) is the rate\u2010limiting enzyme in the salvage pathway. In prior work, we showed that targeting dCK with the small molecule inhibitor TRE\u2010515 limits clinical symptoms in two myelin oligodendrocyte glycoprotein (MOG)\u2010induced experimental autoimmune encephalomyelitis (EAE) mouse models of MS and decreases the levels of activated CD4 T and B lymphocytes in\u00a0vivo. However, whether targeting dCK limits disease in additional EAE models and how targeting dCK directly impacts activated and proliferating CD4 T and B cells has yet to be determined. Here, we show that dCK is activated in the lymph nodes and spleen in an EAE model induced by amino acids 139\u2013151 of the proteolipid protein (PLP<jats:sub>139\u2010151<\/jats:sub>) that is driven by CD4 T and B cells and is characterised by acute disease followed by disease remission. Treating this model with TRE\u2010515 limits clinical symptoms and decreases the levels of activated CD4 T and B cells. In culture, CD4 T and B cells induce deoxyribonucleoside salvage following activation, and TRE\u2010515 directly blocks CD4 T and B cell activation\u2010induced proliferation and activation marker expression. TRE\u2010515 decreases deoxycytidine triphosphate (dCTP) and deoxythymidine triphosphate (dTTP) pools and increases the length of time cells spend in S phase of the cell cycle without inducing a replication stress response in B cells. Our results suggest that dCK activity is required to supply needed dNTPs and to enable rapid cell division following lymphocyte activation against autoantigens in EAE mouse models.<\/jats:p>","DOI":"10.1111\/imm.13885","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T04:45:29Z","timestamp":1734929129000},"page":"247-263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Blocking Deoxycytidine Kinase in Activated Lymphocytes Depletes Deoxycytidine Triphosphate Pools and Alters Cell Cycle Kinetics to Yield Less Disease in a Mouse Multiple Sclerosis Model"],"prefix":"10.1111","volume":"174","author":[{"given":"Jessica R.","family":"Salas","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology UCLA  Los Angeles California USA"},{"name":"Crump Institute for Molecular Imaging UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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