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.

Autor: Salas JR; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.; Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA., Ryan KM; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.; Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA., Trias AO; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.; Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA., Chen BY; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.; Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA., Guemes M; Department of Medicine, UCLA, Los Angeles, California, USA., Galic Z; Department of Medicine, UCLA, Los Angeles, California, USA., Schultz KA; Trethera Corporation, Sherman Oaks, California, USA., Clark PM; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.; Crump Institute for Molecular Imaging, UCLA, Los Angeles, California, USA.
Jazyk: angličtina
Zdroj: Immunology [Immunology] 2024 Dec 22. Date of Electronic Publication: 2024 Dec 22.
DOI: 10.1111/imm.13885
Abstrakt: Autoreactive, aberrantly activated lymphocytes that target myelin antigens in the central nervous system (CNS) are primary drivers of the autoimmune disease multiple sclerosis (MS). 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-limiting enzyme in the salvage pathway. In prior work, we showed that targeting dCK with the small molecule inhibitor TRE-515 limits clinical symptoms in two myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mouse models of MS and decreases the levels of activated CD4 T and B lymphocytes in vivo. 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 139-151 of the proteolipid protein (PLP 139-151 ) that is driven by CD4 T and B cells and is characterised by acute disease followed by disease remission. Treating this model with TRE-515 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-515 directly blocks CD4 T and B cell activation-induced proliferation and activation marker expression. TRE-515 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.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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