IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo

Eur J Immunol. 2014 Jan;44(1):150-61. doi: 10.1002/eji.201343746. Epub 2013 Nov 4.

Abstract

IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6(-/-) mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection.

Keywords: IL-6; Parasite infection; Th2 response; Treg cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Susceptibility
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation / genetics
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nematospiroides dubius / immunology*
  • Parasite Load
  • Phenotype
  • Strongylida Infections / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*
  • Th2 Cells / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antibodies, Blocking
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Interleukin-6
  • Transcription Factors
  • Zfpn1a2 protein, mouse