@article{1dd67857d3e043dbad4cfe9332efb4b6,
title = "FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice",
abstract = "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.",
keywords = "FURIN, CD8 T-cell, LCMV, adaptive immune system, T-cell memory",
author = "Ojanen, {Markus J.T.} and Caro, {Fernanda Munoz} and Saara Aittom{\"a}ki and Ploquin, {Micka{\"e}l J.} and Zsuzsanna Ortutay and Meeri Pekkarinen and Juha Kesseli and Maria V{\"a}h{\"a}tupa and Juuso M{\"a}{\"a}tt{\"a} and Matti Nykter and Junttila, {Ilkka S.} and J{\"a}rvinen, {Tero A.H.} and O'Shea, {John J.} and Biron, {Christine A.} and Marko Pesu",
note = "Funding Information: This work is dedicated to the memory of Christine Biron. We thank the preclinical facility of Tampere University, partly funded by Biocenter Finland, and the preclinical facility of University of Turku for maintaining and providing us with the mice. We also thank Finnish Cell Imaging and Cytometry Centre supported by University of Turku, {\AA}bo Akademi University and Biocenter Finland as well as Biomedicum Functional Genomics Unit at the Helsinki Institute of Life Science and Biocenter Finland at the University of Helsinki. The authors additionally acknowledge the Tampere facility of Flow Cytometry for their service. We especially thank many of our co‐workers for technical assistance and scientific advice. We are grateful for Helen Cooper for proof‐reading the manuscript. 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.), P{\"a}ivikki 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. The graphical abstract was created with BioRender.com. Funding Information: This work is dedicated to the memory of Christine Biron. We thank the preclinical facility of Tampere University, partly funded by Biocenter Finland, and the preclinical facility of University of Turku for maintaining and providing us with the mice. We also thank Finnish Cell Imaging and Cytometry Centre supported by University of Turku, {\AA}bo Akademi University and Biocenter Finland as well as Biomedicum Functional Genomics Unit at the Helsinki Institute of Life Science and Biocenter Finland at the University of Helsinki. The authors additionally acknowledge the Tampere facility of Flow Cytometry for their service. We especially thank many of our co-workers for technical assistance and scientific advice. We are grateful for Helen Cooper for proof-reading the manuscript. 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.), P{\"a}ivikki 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. The graphical abstract was created with BioRender.com. Publisher Copyright: {\textcopyright} 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.",
year = "2023",
month = apr,
doi = "10.1002/eji.202250246",
language = "English",
volume = "53",
journal = "EUROPEAN JOURNAL OF IMMUNOLOGY",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "6",
}