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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • Cells, Cultured
  • Central Nervous System / immunology*
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Disease Models, Animal*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Tumor Necrosis Factor, Type II / physiology*
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha