Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

Autor:	Atretkhany KN; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.; Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.; Institute for Molecular Medicine, University Medical Center of the Johannes Guttenberg University of Mainz, 55131 Mainz, Germany., Mufazalov IA; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.; Institute for Molecular Medicine, University Medical Center of the Johannes Guttenberg University of Mainz, 55131 Mainz, Germany., Dunst J; Research Group Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany., Kuchmiy A; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.; Research Group Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany., Gogoleva VS; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.; Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia., Andruszewski D; Institute for Molecular Medicine, University Medical Center of the Johannes Guttenberg University of Mainz, 55131 Mainz, Germany., Drutskaya MS; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.; Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia., Faustman DL; Department of Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129., Schwabenland M; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany., Prinz M; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany.; BIOSS-Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany., Kruglov AA; Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.; Research Group Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia., Waisman A; Institute for Molecular Medicine, University Medical Center of the Johannes Guttenberg University of Mainz, 55131 Mainz, Germany., Nedospasov SA; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; sergei@nedos.net.; Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.; Research Group Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 18; Vol. 115 (51), pp. 13051-13056. Date of Electronic Publication: 2018 Nov 29.
DOI:	10.1073/pnas.1807499115
Abstrakt:	TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (T reg ) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3 + cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of T reg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished T reg suppressive function in vitro. Consequently, T reg -restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in T reg cells that could translate into protective functions in vivo, including treatment of autoimmunity. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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