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  3. The intrinsic expression of NLRP3 in Th17 cells promotes their protumor activity and conversion into Tregs

The intrinsic expression of NLRP3 in Th17 cells promotes their protumor activity and conversion into Tregs

  • Cell Mol Immunol. 2025 May;22(5):541-556. doi: 10.1038/s41423-025-01281-y.
Théo Accogli 1 2,  Christophe Hibos # 2,  Lylou Milian # 1 2 3,  Mannon Geindreau 1 2,  Corentin Richard 3,  Etienne Humblin 2,  Romain Mary 2,  Sandy Chevrier 3,  Elise Jacquin 1 2,  Antoine Bernard 2,  Fanny Chalmin 4,  Catherine Paul 5 6,  Berhard Ryffel 7,  Lionel Apetoh 8,  Romain Boidot 3,  Mélanie Bruchard 1 2,  François Ghiringhelli 1 2 4 9 10,  Frédérique Vegran 11 12 13 14
Affiliations

Affiliations

  • 1 INSERM, Dijon, France.
  • 2 University of Burgundy, Dijon, France.
  • 3 Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France.
  • 4 Cancer Biology Transfer Platform, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France.
  • 5 LIIC, EA7269, Université de Bourgogne Franche Comté, Dijon, France.
  • 6 Immunology and Immunotherapy of Cancer Laboratory, EPHE, PSL Research University, Paris, France.
  • 7 Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orléans, France.
  • 8 Brown Center for Immunotherapy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 9 Genetic and Immunology Medical Institute, Dijon, France.
  • 10 Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
  • 11 INSERM, Dijon, France. frederique.vegran@inserm.fr.
  • 12 University of Burgundy, Dijon, France. frederique.vegran@inserm.fr.
  • 13 Unité de Biologie Moléculaire-Department of Biology and Pathology of Tumors, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France. frederique.vegran@inserm.fr.
  • 14 Cancer Biology Transfer Platform, Georges-Francois Leclerc Cancer Center-UNICANCER, Dijon, France. frederique.vegran@inserm.fr.
  • # Contributed equally.
PMID: 40195474 DOI: 10.1038/s41423-025-01281-y
Abstract

Th17 cells can perform either regulatory or inflammatory functions depending on the cytokine microenvironment. These plastic cells can transdifferentiate into Tregs during inflammation resolution, in allogenic heart transplantation models, or in Cancer through mechanisms that remain poorly understood. Here, we demonstrated that NLRP3 expression in Th17 cells is essential for maintaining their immunosuppressive functions through an inflammasome-independent mechanism. In the absence of NLRP3, Th17 cells produce more inflammatory cytokines (IFNγ, Granzyme B, TNFα) and exhibit reduced immunosuppressive activity toward CD8+ cells. Moreover, the capacity of NLRP3-deficient Th17 cells to transdifferentiate into Treg-like cells is lost. Mechanistically, NLRP3 in Th17 cells interacts with the TGF-β Receptor, enabling SMAD3 phosphorylation and thereby facilitating the acquisition of immunosuppressive functions. Consequently, the absence of NLRP3 expression in Th17 cells from tumor-bearing mice enhances CD8 + T-cell effectiveness, ultimately inhibiting tumor growth.

Keywords

Cancer Immunology; NLRP3; Th17 cells; Tregs; Tumor microenvironment.

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