Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling
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.
Authors
- Jordi Ochando (ORCID: https://orcid.org/0000-0001-7037-1681)
- Joost H.A. Martens
- Cansu Yanginlar (ORCID: https://orcid.org/0000-0002-0282-1078)
- Luuk B. Hilbrands (ORCID: https://orcid.org/0000-0002-4935-9765)
- Vasiliki Matzaraki (ORCID: https://orcid.org/0000-0002-5852-6801)
- Mihai Gheorghe Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
- Maaike Jacobs (ORCID: https://orcid.org/0000-0002-0292-7219)
- Mandy M. T. van Leent (ORCID: https://orcid.org/0000-0002-9747-1022)
- Leo A. B. Joosten (ORCID: https://orcid.org/0000-0001-6166-9830)
- Anna Ranzenigo (ORCID: https://orcid.org/0000-0002-6771-2577)
- Willem J. M. Mulder (ORCID: https://orcid.org/0000-0001-8665-3878)
- Musa M. Mhlanga (ORCID: https://orcid.org/0000-0003-1381-3409)
- Marijke Baltissen
- Raphaël Duivenvoorden (ORCID: https://orcid.org/0000-0003-1446-8336)
- Y. Negishi (ORCID: https://orcid.org/0000-0002-5134-3957)
- Michiel Vermeulen (ORCID: https://orcid.org/0000-0003-0836-6894)
- Abraham J. P. Teunissen (ORCID: https://orcid.org/0000-0002-0401-8262)
- Johan van der Vlag (ORCID: https://orcid.org/0000-0001-7843-5918)
- Judit Morlà‐Folch (ORCID: https://orcid.org/0000-0003-1059-6939)
- Inge Jonkman
- Nils Rother (ORCID: https://orcid.org/0000-0001-5129-3956)
- William Wang (ORCID: https://orcid.org/0009-0008-3844-2281)
- Rianne Maas (ORCID: https://orcid.org/0000-0003-1521-3116)
- Martin Umali
- Willem Tielemans Zamora
- J. Heck
Institutions
- Radboud University Nijmegen (NL)
- Iuliu Hațieganu University of Medicine and Pharmacy (RO)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- Oncode Institute (NL)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1016/j.celrep.2024.114664
- Citations
- 14
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Radboud Universiteit
- Nierstichting
- Radboud Universitair Medisch Centrum
- National Institutes of Health