Selective reconstitution of IFN‑γ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection
| Autor: | Chintan Chhatbar, Zoe Waibler, Werner Müller, Martin König, Martin Hafner, Pia-Katharina Larsen, Christoph Hirche, Theresa Graalmann, Jennifer Skerra, Gerd Sutter, Klaus Pfeffer, Patrick Blank, Tomas Alanentalo, Veronika Sexl, Julia Spanier, Ulrich Kalinke, Katharina Borst, Sven Flindt |
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| Přispěvatelé: | TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. |
| Rok vydání: | 2020 |
| Předmět: |
Myeloid
Physiology T-Lymphocytes medicine.medical_treatment Gene Identification and Analysis NK cells Pathology and Laboratory Medicine Mice Immune Physiology Immune cells Cytokines Bone marrow cells Gene identification and analysi Virusinfektion Immune response T cells Vaccinia virus Impfstoff Cellular types Vaccinia Antigens Ly Biology (General) Immune Response Innate Immune System 0303 health sciences T Cells 030302 biochemistry & molecular biology Poxviruses Killer Cells Natural medicine.anatomical_structure Cytokine Medical Microbiology Viral Pathogens Viruses White blood cells Pathogens Research Article Cell biology Blood cells QH301-705.5 Transgene Immunology Antigen presentation Bone Marrow Cells Mice Transgenic Biology Microbiology Interferon-gamma 03 medical and health sciences Immune system Antigen Immunity Virology Genetics medicine Animals Microbial Pathogens Molecular Biology 030304 developmental biology Medicine and health sciences Innate immune system Biology and life sciences Natural Cytotoxicity Triggering Receptor 1 Organisms Histocompatibility Antigens Class II RC581-607 Molecular Development Molecular biology Animal cells Gene Expression Regulation Immune System Parasitology Immunologic diseases. Allergy DNA viruses Developmental Biology |
| Zdroj: | PLoS pathogens PLoS Pathogens PLoS Pathogens, Vol 16, Iss 2, p e1008279 (2020) PLoS pathogens, 16(2):e1008279 Borst, K, Flindt, S, Blank, P, Larsen, P-K, Chhatbar, C, Skerra, J, Spanier, J, Hirche, C, König, M, Alanentalo, T, Hafner, M, Waibler, Z, Pfeffer, K, Sexl, V, Sutter, G, Müller, W, Graalmann, T & Kalinke, U 2020, ' Selective reconstitution of IFN‑γ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection ', PLoS Pathogens, vol. 16, no. 2, pp. e1008279 . https://doi.org/10.1371/journal.ppat.1008279 |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1008279 |
| Popis: | IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity. Author summary Viral infections induce interferon (IFN) responses that constitute a first line of defense. Type II IFN (IFN-γ) is required for protection against lethal vaccinia virus (VACV) infection. To address the cellular origin of protective IFN-γ responses during VACV infection, we generated IFN-γOFF mice, in which the endogenous IFN-γ gene function can be reconstituted in a Cre-dependent manner. IFN-γOFF mice were intercrossed with Ncr1-Cre mice that express Cre selectively in Ncr1+ innate cell subsests such as NK cells. Surprisingly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses. Reconstitution of innate IFN-γ was sufficient to restore cytokine responses that supported normal myeloid cell distribution and survival upon VACV infection. In conclusion, IFN-γ derived from Ncr1+ innate immune cells is sufficient to elicit fully effective immune responses upon VACV infection. Our new mouse model is suitable to further address the role of Ncr1+ cell-derived IFN-γ also in other models of infection, as well as of autoimmunity and cancer. |
| Databáze: | OpenAIRE |
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