Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation
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 immu...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54232-y |
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| author | 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 A. Knolle Lawrence Kane Timothy J. Wells Fernando Souza-Fonseca-Guimaraes |
| author_facet | 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 A. Knolle Lawrence Kane Timothy J. Wells Fernando Souza-Fonseca-Guimaraes |
| author_sort | Timothy R. McCulloch |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7d3441596abf4db39ec0dbd7c8ea23d7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7d3441596abf4db39ec0dbd7c8ea23d72024-11-17T12:36:00ZengNature PortfolioNature Communications2041-17232024-11-0115111610.1038/s41467-024-54232-yDichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammationTimothy R. McCulloch0Gustavo R. Rossi1Louisa Alim2Pui Yeng Lam3Joshua K. M. Wong4Elaina Coleborn5Snehlata Kumari6Colm Keane7Andrew J. Kueh8Marco J. Herold9Christoph Wilhelm10Percy A. Knolle11Lawrence Kane12Timothy J. Wells13Fernando Souza-Fonseca-Guimaraes14Frazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandThe Walter and Eliza Hall Institute of Medical ResearchThe Walter and Eliza Hall Institute of Medical ResearchInstitute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of BonnInstitute of Molecular Immunology, School of Medicine and Health, Technical University of MunichDepartment of Immunology, University of Pittsburgh School of MedicineFrazer Institute, The University of QueenslandFrazer Institute, The University of QueenslandAbstract 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.https://doi.org/10.1038/s41467-024-54232-y |
| spellingShingle | 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 A. Knolle Lawrence Kane Timothy J. Wells Fernando Souza-Fonseca-Guimaraes Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation Nature Communications |
| title | Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation |
| title_full | Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation |
| title_fullStr | Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation |
| title_full_unstemmed | Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation |
| title_short | Dichotomous outcomes of TNFR1 and TNFR2 signaling in NK cell-mediated immune responses during inflammation |
| title_sort | dichotomous outcomes of tnfr1 and tnfr2 signaling in nk cell mediated immune responses during inflammation |
| url | https://doi.org/10.1038/s41467-024-54232-y |
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