TNFRp55 controls regulatory T cell responses in Yersinia-induced reactive arthritis

Immunol Cell Biol. 2013 Feb;91(2):159-66. doi: 10.1038/icb.2012.65. Epub 2012 Dec 4.


In addition to its well-known pro-inflammatory effects, tumor necrosis factor (TNF) displays anti-inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (T(reg)) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4(+)CD25(+)FoxP3(+) T(reg) cells in the ReA animal model. The number of T(reg) cells as well as the FoxP3 mRNA expression and interleukin (IL)-10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55(-/-) mice vs wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of T(reg) cell in TNFRp55(-/-) was similar to WT mice. To explore the in vivo function of T(reg) cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4(+) T cells from TNFRp55-deficient mice of day 21, into naïve WT or TNFRp55(-/-) mice. When knockout mice were used as recipients we observed higher delayed-type hypersensitivity (DTH) responses and joint inflammation after heat-killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL-17, interferon (IFN)-γ, IL-6, transforming growth factor (TGF)-β1 and IL-12/23p40 and lower IL-10 levels in RLN of paws challenged with HKY in TNFRp55(-/-) recipient mice. In addition, we found that CD4(+) T cells from TNFRp55(-/-) mice controlled antigen-specific IL-12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of T(reg) cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Arthritis, Reactive / immunology*
  • Arthritis, Reactive / microbiology*
  • Arthritis, Reactive / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Interleukin-10 / biosynthesis
  • Interleukin-12 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Joints / immunology
  • Joints / pathology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mucous Membrane / metabolism
  • Prohibitins
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Necrosis Factor Decoy Receptors / deficiency
  • Tumor Necrosis Factor Decoy Receptors / metabolism*
  • Yersinia / immunology*
  • Yersinia Infections / immunology*
  • Yersinia Infections / microbiology*
  • Yersinia Infections / pathology


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • PHB2 protein, human
  • Prohibitins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Decoy Receptors
  • Interleukin-10
  • Interleukin-12
  • recombinant human tumor necrosis factor-binding protein-1