| Dendritic cells (DCs) are very effective at recognizing, capturing and processing antigens, and after activation, are highly effective antigen presenting cells. DC plays an important role in coordinating innate and adaptive immune response against pathogens. DCs are also likely to balance tolerance and active immunity to commensal microorganisms as part of chronic inflammatory responses.;Two independent studies were conducted to elucidate the role dendritic cells contribute to the tissue integrity. In the first part of my thesis, I found that osteoprotegerin (OPG) knockout (KO) DCs survive better than wild type (WT) DCs and produce more TNF-alpha, IL-12p40, and IL-23 than WT DCs in response to E. coli LPS. This is due to sustained interactions between DCs, which increases both the longevity of OPG KO DCs and the level of proinflammatory cytokines produced by OPG KO DCs. Disruption of DC-DC interactions by OPG treatment reduced both the survival of and cytokine production by WT DCs. In addition, after inoculation with LPS, OPG KO mice produce more TNF-alpha and IL-12p40 than WT mice. My results suggest that OPG regulates survival and cytokine production of DCs, thereby affecting the nature of inflammatory responses.;In the second part of my thesis, I found that all oral bacteria tested could efficiently program DCs. Oral bacteria stimulated human monocyte-derived immature DCs to mature and to secrete cytokines/chemokines. Surprisingly, the most important factor for programming DCs was not whether the oral bacteria were commensals or pathogenic, but whether they were gram-positive or gram negative. Fewer gram-negative bacteria were required than gram-positive bacteria to induce DC maturation. Gram-negative oral bacteria also had a lower threshold for cytokine induction than gram-positive oral bacteria. I also found that the threshold of bacteria required for chemokine induction was 100-1000 fold lower than for inducing cytokines In addition, at very low doses of oral commensal bacteria, monocytes were triggered to migrate toward DC-derived MCP-1. Thus, DC-derived MCP-1 induced in response to oral commensal bacteria may play, at least in part, a role in the maintenance of oral tissue integrity by attracting monocytes. |
