Regulation Of T Cell Immunity By Dendritic Cells

My research work mainly focuses on activation of dendritic cells (DC) byexogenous as well as endogenous agents to translate innate into adaptive immunity. Iand my colleagues in Dr. Sun' lab has investigated pertussis toxin, a microbial agent,drives DC maturation by which it enhances Th1 responses; and Interferon-γ (IFN?γ),an endogenous agent, impairs DC migration possible by which IFN-γ control theoutcome of the immune response. Pertussis toxin (PTX) is an exotoxin produced by Bordetella pertussis, known tohave adjuvant properties that induce Th1 responses. PTX has been widely used as anadjuvant to induce Th1-mediated organ-specific autoimmune diseases in animalmodels. However, the cellular and molecular mechanisms remain to be defined. Inour study, we showed that dendritic cells stimulated with PTX (PTX-DC) were ableto substitute for PTX to promote experimental autoimmune uveitis (EAU). EAUinduced by PTX-DC revealed a typical Th1 response, characterized by highuveitogenic retinal Ag interphotoreceptor retinoidbinding protein (IRBP)-specificIFN-γ and IL-12 production in the draining lymph nodes, as well as increased levelsof anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum ofIRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells toproduce the Th1 cytokine, IFN-γ. After being stimulated with PTX, DC exhibited - 4 -up-regulation of MHC class II, CD80, CD86, CD40, and CD205. PTX-DC had alsoincreased allostimulatory capacity and IL-12 and TNF-α production. Serum IL-12was increased in naive mice that received PTX-DC i.p. In addition, PTX activatedextracellular signal-regulated kinase in DC. Following the inhibition of extracellularsignal-regulated kinase signaling, the maturation of PTX-DC was reduced.Subsequently, the ability of PTX-DC to promote IFN-γ production by T cells in vitroand to induce EAU in vivo was blocked. The results suggest that PTX might exert anadjuvant effect on DC to promote their maturation and the production ofproinflammatory cytokines, thereby eliciting a Th1 response. This mechanism mightexplain why microbial adjuvants or compounds, such as PTX, signal DC to undergothe coordinate maturation events that underlie efficient T cell priming anddifferentiation. Therefore, strategies that target DC activation and modulate DCfunction in vivo may have significant implications for vaccine design and thetreatment of autoimmune disease. Interferon-γ (IFN-γ) is a pleiotrophic cytokine with immunomodulatory effectson a variety of immune cells. Based on the multiple defects of immune cell(macrophage, NK cell) function in mice with disrupted IFN-γ genes and theprotective role of endogenous IFN-γ in certain murine autoimmune disease models,we determined whether dendritic cells (DC) function is aberrant in IFN-γ knockout(GKO) mice. IFN-γ deficiency did not interfere with bone marrow derived DC (BMDC) development and maturation in vitro. BM DC from GKO mice altered cytokinesecretion, chemokine receptor expression, and in vitro migration. Treatment of GKOmice with LPS, known to provoke the recruitment of DC from different organs intothe spleen, enhanced splenic DC population. GKO mice were epicutaneously - 5 -sensitized with the hapten, FITC, and 24 h later many hapten-bearing cellsaccumulated in the draining LNs in GKO mice as compared to wild-typemice. At anearly stage of experimental autoimmune uveitis induction, there was an enhancementof DC number and CD40 expression on cells draining the LNs in immunized GKOmice. In addition, we investigated the effect of IFN-γ on the adaptive immuneresponses in vivo. There was an enhancement of antigen-specific priming T-cells inGKO mice. Moreover, IFN-γ was not required for the development of CD4+CD25+regulatory T cells. Taken together, these data suggest that IFN-γ plays an inhibitoryrole on DC migration and mice with disrupte...