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@ARTICLE{Suen:278998,
      author       = {Suen, Tsz Kin and Al, Burcu and Ulas, Thomas and Reusch,
                      Nico and Bahrar, Harsh and Bekkering, Siroon and Bhat,
                      Jaydeep and Kabelitz, Dieter and Schultze, Joachim L and van
                      de Veerdonk, Frank L and van Lennep, Jeanine Roeters and
                      Riksen, Niels P and Joosten, Leo A B and Netea, Mihai G and
                      Placek, Katarzyna},
      title        = {{H}uman γδ {T} {C}ell {F}unction {I}s {I}mpaired {U}pon
                      {M}evalonate {P}athway {I}nhibition.},
      journal      = {Immunology},
      volume       = {175},
      number       = {3},
      issn         = {0019-2805},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2025-00662},
      pages        = {300 - 322},
      year         = {2025},
      abstract     = {Vδ2 T cells, a predominant human peripheral γδ T cell
                      population, are a promising candidate for the development of
                      immunotherapies against cancer and infected cells.
                      Aminobisphosphonate drugs, such as zoledronate, are commonly
                      used to expand Vδ2 T cells. Yet, such in vitro generated
                      cells have limited efficacy in the clinic. We found that
                      despite inducing excessive proliferation of Vδ2 T cells,
                      zoledronate impaired their effector function and caused the
                      upregulation of the inhibitory receptor TIM3. This effect
                      was due to the inhibition of mevalonate metabolism and
                      dysregulation of downstream biological processes such as
                      protein prenylation and intracellular signalling. In vitro
                      and in vivo inhibition of mevalonate metabolism with
                      zoledronate, statins, and 6-fluoromevalonate, as well as
                      genetic deficiency of the mevalonate kinase, all resulted in
                      compromised cytokine and cytotoxic molecule production by
                      Vδ2 T cells. Impaired Vδ2 T cell function was accompanied
                      by transcriptome and kinome changes. Our findings reveal the
                      importance of mevalonate metabolism for the proper
                      functioning of Vδ2 T cells. This observation provides
                      important considerations for improving their therapeutic use
                      and has repercussions for patients with statin or
                      aminobisphosphonate treatments.},
      keywords     = {Humans / Mevalonic Acid: metabolism / Zoledronic Acid:
                      pharmacology / Receptors, Antigen, T-Cell, gamma-delta:
                      metabolism / Receptors, Antigen, T-Cell, gamma-delta:
                      immunology / Signal Transduction: drug effects / Animals /
                      Mevalonate Kinase Deficiency: immunology / Cells, Cultured /
                      Lymphocyte Activation: drug effects / Phosphotransferases
                      (Alcohol Group Acceptor): genetics / Phosphotransferases
                      (Alcohol Group Acceptor): metabolism /
                      Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
                      / Diphosphonates: pharmacology / Mice / Cytokines:
                      metabolism / Cell Proliferation: drug effects /
                      T-Lymphocytes: immunology / T-Lymphocytes: drug effects /
                      Protein Prenylation: drug effects / Intraepithelial
                      Lymphocytes: immunology / Intraepithelial Lymphocytes: drug
                      effects / Intraepithelial Lymphocytes: metabolism /
                      Hepatitis A Virus Cellular Receptor 2 / T cell (Other) /
                      cytokines (Other) / flow cytometry (Other) / human (Other) /
                      protein kinases/phophatases (Other) / Mevalonic Acid (NLM
                      Chemicals) / Zoledronic Acid (NLM Chemicals) / Receptors,
                      Antigen, T-Cell, gamma-delta (NLM Chemicals) / mevalonate
                      kinase (NLM Chemicals) / Phosphotransferases (Alcohol Group
                      Acceptor) (NLM Chemicals) / Hydroxymethylglutaryl-CoA
                      Reductase Inhibitors (NLM Chemicals) / HAVCR2 protein, human
                      (NLM Chemicals) / Diphosphonates (NLM Chemicals) / Cytokines
                      (NLM Chemicals) / Hepatitis A Virus Cellular Receptor 2 (NLM
                      Chemicals)},
      cin          = {AG Schultze / PRECISE},
      ddc          = {610},
      cid          = {I:(DE-2719)1013038 / I:(DE-2719)1013031},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354) / 352
                      - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-354 / G:(DE-HGF)POF4-352},
      experiment   = {EXP:(DE-2719)PRECISE-20190321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40264329},
      doi          = {10.1111/imm.13931},
      url          = {https://pub.dzne.de/record/278998},
}