E-042. Campylobacter jejuni-Induced Activation of Murine Dendritic Cells Involves Cooperative Signaling through MyD88 and TRIF

V. A. K. Rathinam, D. M. Appledorn, J. D. Olmstead, K. A. Hoag, A. Amalfitano, L. S. Mansfield;
Michigan State Univ., East Lansing, MI.

Campylobacter jejuni is a frequent cause of gastroenteritis in humans. We recently showed that murine bone marrow-derived dendritic cells (BM-DCs) undergo maturation, secrete IL-12 and induce Th1 polarization in response to C. jejuni. Toll-like receptors (TLRs) of DCs are critical in inducing immune responses to pathogens. TLRs activate these responses by signaling through adapters such as MyD88 and TRIF. We hypothesized that maturation and cytokine secretion by BM-DCs in response to C. jejuni are mediated by MyD88 and TRIF signaling and tested whether TLR2 was involved in the responses as well. To test this hypothesis, BM-DCs derived from C57BL/6J wild type (WT), MyD88-, TRIF- or TLR2-deficient mice were exposed to C. jejuni and various responses were assessed. Absence of either MyD88 or TRIF had a significant effect on the expression of MHC-II, co-stimulatory molecules and cytokines. The up regulation of MHC-II and CD86 was significantly decreased in MyD88-, TRIF- and TLR2-deficient DCs when compared to that of WT DCs following C. jejuni challenge. The MyD88-, TRIF- but not TLR2-deficiency also partially inhibited the increase in the expression of CD80. However, increase in expression level of CD40 after C. jejuni exposure was not affected by MyD88-, and TLR2-deficiency but significantly reduced in TRIF-deficient DCs (p < 0.05). IL-12p70 secretion in response to C. jejuni was abolished in MyD88- and TRIF-deficient DCs whereas secretion was only halved in TLR2-deficient DCs. Similarly, secretion of IL-6 and TNF-α following C. jejuni challenge was markedly inhibited by MyD88- and TLR2-deficiency but only marginally reduced by TLR2-deficiency. These data suggest that phenotypic maturation and cytokine production by DCs in response to C. jejuni require MyD88 and TRIF signaling and are partially mediated by TLR2. Most importantly, our results show for the first time that cooperative signaling through MyD88 and TRIF represents a novel mechanism mediating C. jejuni-induced activation of DCs (Funded in whole by contract NIH NO1-AI-30058).