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

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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Proceedings of the National Academy of Sciences of the United States of America. - 115, 51 (2018) , 13051-13056, ISSN: 0027-8424

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2019
• 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.
• Contributor: Institut für Neuropathologie. Freiburg im Breisgau

Further information

• DOI: 10.1073/pnas.1807499115
• URN: urn:nbn:de:bsz:25-freidok-1475529
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:51 PM CET