Ojanen, M.J.T., Caro, F.M., Aittomäki, S., Ploquin, M.J., Ortutay, Z., Pekkarinen, M., Kesseli, J., Vähätupa, M., Määttä, J., Nykter, M., Junttila, I.S., Järvinen, T.A.H., O´Shea, J.J., Biron, C.A. and Pesu, M. (2023), FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice. Eur. J. Immunol., 53: 2250246. https://doi.org/10.1002/eji.202250246
FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice
|Author:||Ojanen, Markus J.T.1; Caro, Fernanda Munoz1; Aittomäki, Saara1;|
1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
2Division of Biology and Medicine, and The Warren Alpert Medical School, Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
3Fimlab Laboratories Ltd, Tampere, Finland
4Faculty of Medicine, University of Oulu, Oulu, Finland
5Department of Clinical Microbiology, Nordlab, Oulu University Hospital, Oulu, Finland
6Tampere University Hospital, Tampere, Finland
7Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
|Online Access:||PDF Full Text (PDF, 4.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe20230922136207
John Wiley & Sons,
|Publish Date:|| 2023-09-22
The proprotein convertase subtilisin/kexins (PCSKs) regulate biological actions by cleaving immature substrate proteins. The archetype PCSK, FURIN, promotes the pathogenicity of viruses by proteolytically processing viral proteins. FURIN has also important regulatory functions in both innate and adaptive immune responses but its role in the CD8+ CTLs remains enigmatic. We used a T-cell-specific FURIN deletion in vivo to demonstrate that FURIN promotes host response against the CTL-dependent lymphocytic choriomeningitis virus by virtue of restricting viral burden and augmenting interferon gamma (IFNG) production. We also characterized Furin KO CD8+ T cells ex vivo, including after their activation with FURIN regulating cytokines IL12 or TGFB1. Furin KO CD8+ T cells show an inherently activated phenotype characterized by the upregulation of effector genes and increased frequencies of CD44+, TNF+, and IFNG+ cells. In the activated CTLs, FURIN regulates the productions of IL2, TNF, and GZMB and the genes associated with the TGFBR-signaling pathway. FURIN also controls the expression of Eomes, Foxo1, and Bcl6 and the levels of ITGAE and CD62L, which implies a role in the development of CTL memory. Collectively, our data suggest that the T-cell expressed FURIN is important for host responses in viral infections, CTL homeostasis/activation, and memory development.
European journal of immunology
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This study was financially supported by the Academy of Finland (Grant Nos. 295814 to M.J.T.O./Ma.P., 25013080481 and 25013142041 to I.S.J.), the Cancer Foundation of Finland (Grant Nos. 180138 to Ma.P.; 190146 to M.J.T.O./Ma.P.), the Paulo Foundation (M.J.T.O.), Tampere ImmunoExcellence-Vaccines and Immunomodulation Platform (M.J.T.O.), the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital/ Fimlab Laboratories (Grant Nos. X50070 to Ma.P.; X51409 to I.S.J., 9X011 and 9V010 to T.A.H.J.), Tampere University Hospital Support Foundation (I.S.J.), Päivikki and Sakari Sohlberg Foundation (T.A.H.J.), and Tampere Tuberculosis Foundation (M.J.T.O., T.A.H.J., and I.S.J.). The funding parties were not involved in the study design, in the collection, analysis or interpretation of the data, in the writing of the report or in the decision to submit the article for publication.
RNA sequencing data has been submitted to the Gene Expression Omnibus (GEO) repository (identifier code: GSE186813). Other generated and analyzed data are available on reasonable request from the corresponding author.
© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.