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  3. Metallophilic marginal zone macrophages cross-prime CD8+ T cell-mediated protective immunity against blood-borne tumors

Metallophilic marginal zone macrophages cross-prime CD8+ T cell-mediated protective immunity against blood-borne tumors

  • Immunity. 2025 Apr 8;58(4):843-860.e20. doi: 10.1016/j.immuni.2025.02.027.
François-Xavier Mauvais 1,  Yamina Hamel 2,  Aymeric Silvin 3,  Kevin Mulder 3,  Kai Hildner 4,  Ramazan Akyol 5,  Marc Dalod 5,  Despoina Koumantou 6,  Loredana Saveanu 6,  Meriem Garfa 7,  Nicolas Cagnard 8,  Barbara Bertocci 2,  Florent Ginhoux 9,  Peter van Endert 10
Affiliations

Affiliations

  • 1 Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, 75015 Paris, France; Service de Physiologie - Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, 75019 Paris, France. Electronic address: francois-xavier.mauvais@inserm.fr.
  • 2 Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, 75015 Paris, France.
  • 3 Gustave Roussy Cancer Campus, Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France.
  • 4 University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Medical Department 1, Deutsches Zentrum Immuntherapie, 91054 Erlangen, Germany.
  • 5 Aix Marseille Université, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France.
  • 6 Université Paris Cité, Centre de recherche sur l'inflammation, INSERM UMR1149, CNRS EMR8252, Faculté de Médecine site Bichat, 75018 Paris, France; Université Paris Cité, Laboratoire d'Excellence Inflamex, 75018 Paris, France.
  • 7 Cell Imaging, Structure Fédérative de Recherche Necker, INSERM, US24/CNRS UMS3633, 75015 Paris, France.
  • 8 Bioinformatics Core Facilities, Structure Fédérative de Recherche Necker, INSERM, US24/CNRS UMS3633, 75015 Paris, France.
  • 9 Gustave Roussy Cancer Campus, Villejuif, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France; Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research, (A∗STAR), Singapore, Singapore; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore.
  • 10 Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, 75015 Paris, France; Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France. Electronic address: peter.van-endert@inserm.fr.
PMID: 40139188 DOI: 10.1016/j.immuni.2025.02.027
Abstract

Splenic metallophilic marginal zone macrophages (MMMs) are positioned to control the dissemination of blood-borne threats. We developed a purification protocol to enable characterization of MMMs phenotypically and transcriptionally. MMM gene expression profile was enriched for pathways associated with CD8+ T cell activation and major histocompatibility complex class I (MHC class I) cross-presentation. In vitro, purified MMMs equaled conventional dendritic cells type 1 (cDC1s) in cross-priming CD8+ T cells to soluble and particulate antigens, yet MMMs employed a distinct vacuolar processing pathway. In vivo biphoton and ex vivo light-sheet imaging showed long-standing contacts with cognate T cells differentiating to effectors. MMMs cross-primed protective CD8+ T cell antitumor responses both by capturing blood-borne tumor antigens and by internalizing tumor cells seeding the spleen. This cross-priming required expression of the transcription factor Batf3 by MMMs but was independent of cDC1-mediated capture of tumor material for cross-presentation or MHC class I-dressing. Thus, MMMs combine control of the dissemination of blood-borne pathogens and tumor Materials with the initiation of innate and adaptive responses.

Keywords

MHC class I; antigen cross-presentation; cytotoxic T lymphocytes; immune response; macrophage; marginal zone; spleen; tumor response; vacuolar processing pathway.

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