Cellular mechanisms involved in host responses to Porphyromonas gingivalis and its virulence factor hemagglutinin B.

摘要

Porphyromonas gingivalis is a main causative agent for adult chronic periodontitis and immunization with its virulence factor Hemagglutinin B (HagB) provides protection against infection. Toll-like receptors (TLRs) recognize various microbial products and are crucial in eliciting and regulating the innate and adaptive immune responses to infections. The objective of this dissertation was to investigate the cellular mechanisms that influence the innate and adaptive immune response to HagB and P. gingivalis, focusing on the role of TLR signaling in the response. We started with investigating the ability of HagB to activate dendritic cells (DC), the most efficient antigen-presenting cell in priming naive CD4 T cells, and the role TLR signaling played in this response. Our results showed that HagB induced DC maturation in a TLR4 dependent manner and required adaptor molecules MyD88 and TRIF for an optimal response.;Second, we investigated the requirement of TLR4 signaling in shaping the CD4 T cell response to HagB. Our results showed that HagB immunization primed a CD4 T cell response that responded to P. gingivalis stimulation by IFN-gamma production. TLR4 signaling shaped the type of CD4 T cell and antibody response induced and regulated the expression of transcription factors, T-bet, GATA3, and Foxp3, and the IL-2/STAT5 signaling pathway. MyD88 and TRIF played differential regulatory roles downstream of TLR4 in shaping the CD4 T cell response.;Third, we investigated the role of Interleukin 10 (IL-10) in inhibiting the CD4 T cell response to P. gingivalis. Our results showed that CD4+CD25- T cells produced IL-10 and upregulated Foxp3 in response to P. gingivalis in a TLR2 dependent manner. Upon neutralization of IL-10, CD4+CD25- T cells produced substantial amounts of IFN-gamma and upregulated T-bet. The results from these studies suggest that the immune response to HagB and P. gingivalis is tightly regulated by inflammatory signals mediated by TLR4 and IFN-gamma, and inhibitory signals mediated by TLR2 and IL-10. The proper understanding of the mechanisms governing the balance between these inflammatory and inhibitory pathways can provide us with necessary information for effective design of strategies to fight periodontal diseases.;Keywords: Toll-like receptors, P. gingivalis, Hemagglutinin, CD4 T cells.