Engagement of Toll‐like receptor 2 enhances interleukin ( IL )‐17 + autoreactive T cell responses via p38 mitogen‐activated protein kinase signalling in dendritic cells

Summary Functional analysis of single Toll‐like receptors ( TLRs ) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR‐ 2 agonists on the autoreactive T helper type 17 ( Th 17) response in experimental autoimmune uveitis ( EAU ). Treatment by peptidoglycan ( PGN ), a specific TLR‐ 2 agonist, remarkably increased mRNA levels of Th 17‐lineage genes interleukin ( IL )‐17 A , IL ‐21 and RAR‐related orphan receptor (RO R )γt and promoted antigen‐specific Th 17 response in EAU mice. A mixture of PGN and interphotoreceptor retinoid‐binding protein peptide ( IRBP 161–180 ) could effectively induce EAU in the absence of complete Freund's adjuvant ( CFA ). PGN treatment also enhanced the pathogenic activities of activated antigen‐specific Th 17 cells in vivo . PGN significantly increased the production of IL ‐1β, IL ‐6 and IL ‐23 of dendritic cells ( DCs ) and enhanced their ability to promote IL ‐17 + uveitogenic T cells. Enhanced immunostimulatory activities of PGN ‐ DCs depend upon p38 activation. Inhibition of p38 mitogen‐activated protein kinase ( MAPK ) activity dramatically decreased IL ‐17 gene expression and antigen‐specific Th 17 responses stimulated by PGN ‐ DCs . Our findings suggest that PGN treatment dramatically promotes the IL ‐17 + uveitogenic T cell responses via enhancing the immunostimulatory activities of DCs . This effect may be mediated, at least in part, by activation of the p38 signalling pathway in DCs .