2. Academic Validation
  3. Splenic TNF-α signaling potentiates the innate-to-adaptive transition of antiviral NK cells

Splenic TNF-α signaling potentiates the innate-to-adaptive transition of antiviral NK cells

  • Immunity. 2025 Mar 11;58(3):585-600.e6. doi: 10.1016/j.immuni.2025.02.012.
Adriana M Mujal 1,  Mark Owyong 2,  Endi K Santosa 2,  John C Sauter 3,  Simon Grassmann 3,  Anna-Marie Pedde 4,  Philippa Meiser 5,  Claire K Wingert 3,  Marine Pujol 6,  Veit R Buchholz 6,  Colleen M Lau 3,  Jan P Böttcher 4,  Joseph C Sun 7
Affiliations

Affiliations

  • 1 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: mujala@mskcc.org.
  • 2 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
  • 3 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Department of Experimental Immunology, Institute of Immunology, University of Tübingen, Tübingen, Germany; M3 Research Center, University Hospital Tübingen, University of Tübingen, Tübingen, Germany; Institute of Molecular Immunology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
  • 5 Institute of Molecular Immunology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
  • 6 Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
  • 7 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA. Electronic address: sunj@mskcc.org.
PMID: 40023159 DOI: 10.1016/j.immuni.2025.02.012
Abstract

Natural killer (NK) cells possess both innate and adaptive features. Here, we investigated NK cell activation across tissues during cytomegalovirus Infection, which generates antigen-specific clonal expansion and long-lived memory responses. Longitudinal tracking and single-cell RNA Sequencing of NK cells following Infection revealed enhanced activation in the spleen, as well as early formation of a CD69lo precursor population that preferentially gave rise to adaptive NK cells. Splenic NK cells demonstrated heightened tumor necrosis factor alpha (TNF-α) signaling and increased expression of the receptor TNFR2, which coincided with elevated TNF-α production by splenic myeloid cells. TNFR2-deficient NK cells exhibited impaired interferon gamma (IFN-γ) production and expansion. TNFR2 signaling engaged two distinct nuclear factor κB (NF-κB) signaling arms-innate effector NK cell responses required canonical NF-κB signaling, whereas non-canonical NF-κB signaling enforced differentiation of CD69lo adaptive NK cell precursors. Thus, NK cell priming in the spleen during viral Infection promotes an innate-to-adaptive transition, providing insight into avenues for generating adaptive NK cell immunity across diverse settings.

Keywords

MCMV; NF-κB signaling; NIK; NK cells; TNF-α; TNFR2.

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