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

McCulloch, TR; Rossi, GR; Alim, L; Lam, PY; Wong, JKM; Coleborn, E; Kumari, S; Keane, C; Kueh, AJ; Herold, MJ; Wilhelm, C; Knolle, PA; Kane, L; Wells, TJ; Souza-Fonseca-Guimaraes, F

Author(s): McCulloch, TR; Rossi, GR; Alim, L; Lam, PY; Wong, JKM; Coleborn, E; Kumari, S; Keane, C; Kueh, AJ; Herold, MJ; Wilhelm, C; Knolle, PA; Kane, L; Wells, TJ; Souza-Fonseca-Guimaraes, F;
Details: Publication Year 2024-11-14,Volume 15,Issue #1,Page 9871
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Animals; *Killer Cells, Natural/immunology; *Receptors, Tumor Necrosis Factor, Type I/metabolism/genetics; *Receptors, Tumor Necrosis Factor, Type II/metabolism/genetics; *Signal Transduction; *Inflammation/immunology/metabolism; Mice; *Mice, Inbred C57BL; Hepatitis A Virus Cellular Receptor 2/metabolism/genetics; Salmonella typhimurium/immunology; Mice, Knockout; Salmonella Infections/immunology; Tumor Necrosis Factor-alpha/metabolism; Male; Female
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 39543125
Publisher's Version: https://doi.org/10.1038/s41467-024-54232-y
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-54232-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-12-05 11:26:39

Last Modified: 2024-12-05 01:09:45