Commensal microbes drive intestinal inflammation by IL-17-producing CD4+ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2
Abstract
T-cell activation requires cognate antigen encounter plus additional stimulation through B7 costimulatory molecules. This explains why B7 costimulation blockade is therapeutically effective in many autoimmune disorders including diabetes and rheumatoid arthritis. Interestingly, however, intestinal inflammation is uniquely resistant to B7-neutralizing therapies. We show that colonization with commensal bacteria predisposes the intestine to inflammation despite B7 deprivation caused by IL-17-producing T cells that become activated through the acces-sory costimulation molecules ICOSL and OX40L. Reciprocally, intestinal inflammation is silenced when either commensal enteric bacteria or stimulation through ICOSL/OX40L is eliminated. These results suggest that simultaneously neutralizing accessory costimulation molecules may be needed to extinguish inflammation in tissues like the intestine that retain prominent B7-independent pathways for T-cell activation.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- July 2014
- DOI:
- 10.1073/pnas.1402336111
- Bibcode:
- 2014PNAS..11110672X