The liver is unique in its immunologic properties. Although dendritic cells (DC) are known to be critical regulators of the immune system, little is known about normal liver DC. We have determined that bulk murine liver DC are functionally distinct from bulk spleen DC. We have also identified 5 subtypes of freshly isolated liver DC. One subtype is plasmacytoid DC, which we found to be relatively abundant in the liver as compared to the spleen. We have discovered that liver and spleen plasmacytoid DC have disparate function. Steady state liver plasmacytoid DC are less mature and induce less allogeneic and antigen specific T cell activation. Upon stimulation, liver plasmacytoid DC secrete large amounts of TNF-alpha and IFN-alpha unlike spleen plasmacytoid DC, which make large quantities of IL-10. We hypothesize that liver plasmacytoid DC normally contribute to tolerance in the liver. However, because liver plasmacytoid DC can be stimulated to secrete pro-inflammatory cytokines, we postulate that they are also capable of inducing immunity.
In Aim 1, we will determine the mechanism of interaction between liver plasmacytoid DC and T cells. We will employ an established murine model of intravenous adoptive transfer of TCR transgenic T cells and footpad injection of dendritic cells. We will determine if liver plasmacytoid DC induce T cell anergy, deletion, or suppression by studying the T helper response and delayed type hypersensitivity reaction.
In Aim 2, we will ascertain whether liver plasmacytoid DC are necessary for liver tolerance by developing a model of injecting antigen loaded liver plasmacytoid DC into the portal vein of mice. We will also directly test the importance of liver plasmacytoid DC in portal vein tolerance in vivo by using a depleting antibody.
In Aim 3, we will study the mechanism of interaction between stimulated liver plasmacytoid DC and T cells and how it is affected by DC cytokine secretion. We will determine whether stimulation of liver plasmacytoid DC prevents their induction of tolerance. The proposed experiments will define further the biology of liver dendritic cells and their interaction with T cells, as well as advance our understanding of tolerance and immunity. We expect the findings to be important for immunologic conditions of the liver that include autoimmunity, infection, transplantation, and cancer.
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