TLR2 Mediated CD39+Treg Induction by a Human Gut Commensal Antigen Protects EAE Mice and Restores Impaired Treg Function in Man (P05.107)

Abstract

Objective: To assess the role for gut commensal bacteria in CNS demyelination. Background Our understanding for the role of the gut microbiota in the control of autpimmunity is evolving. We have identified a polysaccharide (PSA) produced by the human commensal B.fragilis that confers protection to EAE in mice. Gut associated CD103+ dendritic cells (DCs) accumulate within the CLN of PSA immunized EAE mice. These CD103+ DCs enhance the conversion of naive CD4+ T cells into protective IL-10-producing FoxP3+ T cells. The role of gut commensal microbiota in human MS has yet to be established. Design/Methods: CD103+/- DCs were co-cultured with CLN isolated CD4+ T cells in the presence of purified PSA (100 μg/ml). FoxP3+CD39+ and IL-10 production by CD4+T cells was determined by FACS and ELISA. Fluorochrome labeled PSA was used to identify the DC subpopulations from the PBMC that was associated with PSA uptake. PBMC were isolated from those with defined RRMS naive or off treatment x 30 days. Results: TLR2 deficiency impaired uptake of PSA. CD103+DCs from intact mice but not TLR2-/- provoked the acquisition of sFoxP3+ phenotype. PBMCs from TLR2 deficient mice were unable to convert CD4+ T cells into FoxP3+Tregs. TLR2 was critical for the IL-10 production as well as the upregulation of CD39+ Tregs in both humans with MS and EAE mice. The protection induced by oral immunization with PSA was abrogated in TLR2 mice confirming the essential role of TLR2 protection elicited PSA. Conclusions: TLR2 signaling is essential in the experimental protection by the human B. fragilis antigen PSA. This antigen can induce IL-10+ secreting CD39+ Tregs in both humans with MS and mice with EAE. The induction of this regulatory phenotype and cytokine profile by PSA could potentially act as therapeutic for the restoration of the Treg impaired function in those with MS. Supported by: NMSS Center of Collaboration and the Murray Bornstein Fellowship. Disclosure: Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation. Dr. Ochoa-Reparaz has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Begum-Haque has received research support from Teva Neuroscience. Dr. Mielcarz has nothing to disclose.