An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling

Nat Commun. 2014 Jul 21;5:4432. doi: 10.1038/ncomms5432.

Abstract

The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. The intestinal microbiome can influence host susceptibility to extra-intestinal autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for the human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through Toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39(+) CD4 T-cell subset by PSA. Ablation of CD39 signalling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3(+) CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apyrase / genetics
  • Apyrase / metabolism*
  • Bacteroides fragilis / physiology
  • CD4-Positive T-Lymphocytes / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / etiology*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inflammation / metabolism*
  • Intestinal Mucosa / metabolism
  • Intestines / immunology
  • Intestines / microbiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis
  • Polysaccharides, Bacterial / metabolism*
  • Signal Transduction
  • Symbiosis
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*

Substances

  • Antigens, CD
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Polysaccharides, Bacterial
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Apyrase
  • CD39 antigen