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

• Published in: European journal of immunology 2014-01, Vol.44 (1), p.150-161
• Main Authors: Smith, Katherine A., Maizels, Rick M.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Blocking - administration & dosage; Cells, Cultured; Disease Susceptibility; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene Expression Regulation - genetics; Genotype & phenotype; IL‐6; Immunity to Infection; Infections; 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 infection; Parasite Load; Phenotype; Rodents; Strongylida Infections - immunology; T cell receptors; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Th2 Cells - immunology; Th2 response; Transcription Factors - genetics; Transcription Factors - metabolism; Treg cells
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201343746

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.