2. Academic Validation
  3. Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling

Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling

  • Cell Rep. 2024 Sep 24;43(9):114664. doi: 10.1016/j.celrep.2024.114664.
Maaike M E Jacobs 1,  Rianne J F Maas 2,  Inge Jonkman 1,  Yutaka Negishi 3,  Willem Tielemans Zamora 4,  Cansu Yanginlar 1,  Julia van Heck 5,  Vasiliki Matzaraki 5,  Joost H A Martens 6,  Marijke Baltissen 6,  Michiel Vermeulen 6,  Judit Morla-Folch 4,  Anna Ranzenigo 4,  William Wang 4,  Martin Umali 4,  Jordi Ochando 7,  Johan van der Vlag 1,  Luuk B Hilbrands 1,  Leo A B Joosten 8,  Mihai G Netea 9,  Willem J M Mulder 10,  Mandy M T van Leent 11,  Musa M Mhlanga 3,  Abraham J P Teunissen 12,  Nils Rother 1,  Raphaël Duivenvoorden 13
Affiliations

Affiliations

  • 1 Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 2 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 3 Department of Cell Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 6 Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands.
  • 7 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Transplant Immunology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
  • 8 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, University of Medicine and Pharmacy, Iuliu Haţieganu, Cluj-Napoca, Romania.
  • 9 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • 10 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
  • 11 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12 BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 13 Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: raphael.duivenvoorden@radboudumc.nl.
PMID: 39178113 DOI: 10.1016/j.celrep.2024.114664
Abstract

Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

Keywords

CD40-CD40L; CP: Immunology; T cells; innate immunity; monocytes; nanobiologics; trained immunity.

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