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Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13051-13056. doi: 10.1073/pnas.1807499115. Epub 2018 Nov 29.

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

Author information

1
Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
2
Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.
3
Institute for Molecular Medicine, University Medical Center of the Johannes Guttenberg University of Mainz, 55131 Mainz, Germany.
4
Research Group Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, 10117 Berlin, Germany.
5
Department of Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
6
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, D-79106 Freiburg, Germany.
7
BIOSS-Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
8
CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
9
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.
10
Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; sergei@nedos.net.

Abstract

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 (Treg) 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 Treg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished Treg suppressive function in vitro. Consequently, Treg-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 Treg cells that could translate into protective functions in vivo, including treatment of autoimmunity.

KEYWORDS:

EAE; T regulatory cells; TNF/TNFR2; humanized mice; neuroinflammation

PMID:
30498033
PMCID:
PMC6304938
DOI:
10.1073/pnas.1807499115
[Indexed for MEDLINE]
Free PMC Article

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