| Campylobacter jejuni is a clinically significant food-borne pathogen that causes enteritis. Dendritic cells (DCs) are central to initiating immune responses to pathogens. One objective of this study was to understand the interaction of murine DCs with C. jejuni and its impact on induction of T cell responses mediating resistance. Following infection with C. jejuni, DCs were found to efficiently kill C. jejuni and undergo activation by up regulating the surface expression of maturation markers and by secreting IL-12, IL-6 and TNF-alpha. Notably, C. jejuni-infected DCs induced Th1-differentiation of naive CD4+T cells. Next, we investigated the role of toll-like receptor (TLR) signaling in mediating these responses. Upregulation of maturation markers was significantly impaired in both TLR2-/- and TLR4-/- DCs relative to wild type (WT) DCs after C. jejuni challenge. In contrast, TLR4 deficiency, but not TLR2 deficiency, profoundly impaired the cytokine responses following C. jejuni infection. Because TLR4 utilizes both MyD88 and TRIF adapters for signal transduction, we investigated the role of MyD88 and TRIF in these responses. The expression of maturation markers and cytokines in response to C. jejuni was greatly reduced in the absence of either MyD88 or TRIF. Furthermore, C. jejuni infection induced IRF-3 phosphorylation and IFN-beta secretion by DCs in a TLR4-TRIF dependent fashion, further demonstrating activation of this pathway by C. jejuni. Importantly, TLR2, TLR4, MyD88, and TRIF deficiencies all markedly impaired Th1-priming ability of C. jejuni -infected DCs. Thus, our results show for the first time that cooperative signaling through MyD88-dependent and -independent (TRIF) arms of the TLR4 signaling represents a novel mechanism mediating C. jejuni-induced inflammatory activation of DCs. |
