Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Autor: Scherer S; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.; Formerly Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland., Oberle SG; Formerly Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.; Sanofi Genzyme, Baar, Switzerland., Kanev K; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Gerullis AK; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Wu M; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., de Almeida GP; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Puleston DJ; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany., Baixauli F; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany., Aly L; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, Munich, Germany.; Department of Neurology, Technical University of Munich School of Medicine, Munich, Germany., Greco A; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Nizharadze T; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Becker NB; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Hoesslin MV; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Donhauser LV; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Berner J; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Chu T; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., McNamara HA; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Esencan Z; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.; Medpace Germany, Munich, Germany., Roelli P; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.; Spatial Transcriptomics AB, Stockholm, Sweden., Wurmser C; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany., Kleiter I; Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg, Germany.; Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany., Vehreschild MJGT; Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany., Mayer CA; Neurologische Gemeinschaftspraxis am Kaiserplatz, Frankfurt, Germany., Knolle P; Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany.; German Center for Infection Research (DZIF), Munich, Germany.; Institute of Molecular Immunology, School of Life Science, Technical University of Munich (TUM), Munich, Germany., Klingenspor M; Chair for Molecular Nutritional Medicine, School of Life Sciences, Technical University of Munich, Freising, Germany., Fumagalli V; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Iannacone M; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Prlic M; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, USA.; Department of Global Health, University of Washington, Seattle, WA, USA., Korn T; Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine, Munich, Germany.; Department of Neurology, Technical University of Munich School of Medicine, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Pearce EL; Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA., Höfer T; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Schulz AM; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. anna.schulz@tum.de., Zehn D; Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. dietmar.zehn@tum.de.; Formerly Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland. dietmar.zehn@tum.de.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2023 Mar; Vol. 24 (3), pp. 501-515. Date of Electronic Publication: 2023 Feb 16.
DOI: 10.1038/s41590-023-01436-x
Abstrakt: Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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