Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity
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 dis...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (51), p.13051-13056 |
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| creator | Atretkhany, Kamar-Sulu N. Mufazalov, Ilgiz A. Dunst, Josefine Kuchmiy, Anna Gogoleva, Violetta S. Andruszewski, David Drutskaya, Marina S. Faustman, Denise L. Schwabenland, Marius Prinz, Marco Kruglov, Andrey A. Waisman, Ari Nedospasov, Sergei A. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1807499115 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1807499115</identifier><identifier>PMID: 30498033</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Autoimmune diseases ; Biological Sciences ; CD25 antigen ; CTLA-4 protein ; Cytokines ; Deactivation ; Experimental allergic encephalomyelitis ; Foxp3 protein ; Helper cells ; Immune response ; Immunoregulation ; Inactivation ; Lymphocytes T ; Mice ; Molecules ; Pathogenesis ; Phenotypes ; Receptors ; Rodents ; Signaling ; T cell receptors ; Tumor necrosis factor ; Tumor necrosis factor receptors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-12, Vol.115 (51), p.13051-13056</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright © 2018 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Dec 18, 2018</rights><rights>Copyright © 2018 the Author(s). Published by PNAS. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-9b67ddf9fc02886f6114c7c7e0b731e8fd0719750ad673d2bbb289aee88a4e1a3</citedby><cites>FETCH-LOGICAL-c443t-9b67ddf9fc02886f6114c7c7e0b731e8fd0719750ad673d2bbb289aee88a4e1a3</cites><orcidid>0000-0001-9332-0131 ; 0000-0001-7277-736X ; 0000-0002-2286-0269</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26574219$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26574219$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30498033$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Atretkhany, Kamar-Sulu N.</creatorcontrib><creatorcontrib>Mufazalov, Ilgiz A.</creatorcontrib><creatorcontrib>Dunst, Josefine</creatorcontrib><creatorcontrib>Kuchmiy, Anna</creatorcontrib><creatorcontrib>Gogoleva, Violetta S.</creatorcontrib><creatorcontrib>Andruszewski, David</creatorcontrib><creatorcontrib>Drutskaya, Marina S.</creatorcontrib><creatorcontrib>Faustman, Denise L.</creatorcontrib><creatorcontrib>Schwabenland, Marius</creatorcontrib><creatorcontrib>Prinz, Marco</creatorcontrib><creatorcontrib>Kruglov, Andrey A.</creatorcontrib><creatorcontrib>Waisman, Ari</creatorcontrib><creatorcontrib>Nedospasov, Sergei A.</creatorcontrib><title>Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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. 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30498033</pmid><doi>10.1073/pnas.1807499115</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-9332-0131</orcidid><orcidid>https://orcid.org/0000-0001-7277-736X</orcidid><orcidid>https://orcid.org/0000-0002-2286-0269</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Autoimmune diseases Biological Sciences CD25 antigen CTLA-4 protein Cytokines Deactivation Experimental allergic encephalomyelitis Foxp3 protein Helper cells Immune response Immunoregulation Inactivation Lymphocytes T Mice Molecules Pathogenesis Phenotypes Receptors Rodents Signaling T cell receptors Tumor necrosis factor Tumor necrosis factor receptors |
| title | Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity |
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