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Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation

Author

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  • Timothy R. McCulloch

    (The University of Queensland
    University of Bonn)

  • Gustavo R. Rossi

    (The University of Queensland)

  • Louisa Alim

    (The University of Queensland)

  • Pui Yeng Lam

    (The University of Queensland)

  • Joshua K. M. Wong

    (The University of Queensland)

  • Elaina Coleborn

    (The University of Queensland)

  • Snehlata Kumari

    (The University of Queensland)

  • Colm Keane

    (The University of Queensland
    Princess Alexandra Hospital)

  • Andrew J. Kueh

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marco J. Herold

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Olivia Newton-John Cancer Research Institute)

  • Christoph Wilhelm

    (University of Bonn)

  • Percy A. Knolle

    (Technical University of Munich)

  • Lawrence Kane

    (University of Pittsburgh School of Medicine)

  • Timothy J. Wells

    (The University of Queensland
    University of Queensland)

  • Fernando Souza-Fonseca-Guimaraes

    (The University of Queensland)

Abstract

Natural killer (NK) cell function is regulated by a balance of activating and inhibitory signals. Tumor necrosis factor (TNF) is an inflammatory cytokine ubiquitous across homeostasis and disease, yet its role in regulation of NK cells remains unclear. Here, we find upregulation of the immune checkpoint protein, T cell immunoglobulin and mucin domain 3 (Tim3), is a biomarker of TNF signaling in NK cells during Salmonella Typhimurium infection. In mice with conditional deficiency of either TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) in NK cells, we find TNFR1 limits bacterial clearance whereas TNFR2 promotes it. Mechanistically, via single cell RNA sequencing we find that both TNFR1 and TNFR2 induce the upregulation of Tim3, while TNFR1 accelerates NK cell death but TNFR2 promotes NK cell accumulation and effector function. Our study thus highlights the complex interplay of TNF-based regulation of NK cells by the two TNF receptors during inflammation.

Suggested Citation

  • Timothy R. McCulloch & Gustavo R. Rossi & Louisa Alim & Pui Yeng Lam & Joshua K. M. Wong & Elaina Coleborn & Snehlata Kumari & Colm Keane & Andrew J. Kueh & Marco J. Herold & Christoph Wilhelm & Percy, 2024. "Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54232-y
    DOI: 10.1038/s41467-024-54232-y
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    1. Isaac Dean & Colin Y. C. Lee & Zewen K. Tuong & Zhi Li & Christopher A. Tibbitt & Claire Willis & Fabrina Gaspal & Bethany C. Kennedy & Veronika Matei-Rascu & Rémi Fiancette & Caroline Nordenvall & Ul, 2024. "Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
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