Title: Biology of Fc(epsilon)RI expression on plasmacytoid dendritic cells
Description: Plasmacytoid dendritic cells (pDCs) are highly specialized inflammatory mediators that play a crucial role in Thl-type anti-viral immune responses. Recently, pDCs were shown to be specifically recruited to allergen-challenged human nasal tissue in situ suggesting a role for pDCs in Th2-type allergic inflammation. To investigate the potential role of pDCs in allergic inflammation we sought to (1) identify IgE-binding structures expressed on pDCs and (2) investigate the utility of a previously-generated transgenic mouse engineered to express the high-affinity receptor for IgE, Fc[varepsilon]RI, on immune effector cells as an in vivo model for Fc[varepsilon]RI-mediated antigen presentation. We report that pDCs isolated from the blood of allergic volunteers bind relatively high levels of monomeric IgE via surface Fc[varepsilon]RI. Furthermore, Fc[varepsilon]RI-expressing pDCs internalize Fc[varepsilon]RI surface complexes in response to hIgE immune complexes (IC) suggesting a potential role for Fc[varepsilon]RI on pDCs in allergen presentation. In addition, we report that mice transgenic for Fc[varepsilon]RI preferentially express Fc[varepsilon]RI on splenic macrophages, CD11c hi dendritic cells, and B220 + pDCs. We show that in response to ova-specific IgE IC, Fc[varepsilon]RI-expressing bone marrow-derived pDC precursor cells (BMDCs): (1) internalize surface Fc[varepsilon]RI complexes, (2) induce tyrosine phosphorylation of cellular substrates, and (3) exhibit a specific influx of intracellular free calcium yet fail to induce the proliferation of ova-specific CD4 + T cells in vitro.

Additionally, Fc[varepsilon]RI-expressing BMDCs do not modulate expression of selected immunomodulatory cytokines or costimulatory molecules in response to IgE IC in vitro. Moreover, Fc[varepsilon]RI ligation on Fc[varepsilon]RI-expressing BMDCs does not induce a specific transcriptional profile at 24 or 48 hours post-ligation strongly suggesting that BMDCs from BALB/c H-2d Fc[varepsilon]RItransgenic mice fail to integrate Fc[varepsilon]RI-induced signals. However, in response to ova-specific IgE IC, Fc[varepsilon]RI-transgenic BMDCs from C57BL/6 H-2 b mice induce the proliferation of ova-specific TCR-tg CD4 + T cells at least 10X more efficiently than when BMDCs were pulsed with soluble ovalbumin in vitro. Taken together, these data potentiate the utility of C57BL/6 H-2 b Fc[varepsilon]RI-transgenic mice as a unique tool to investigate the specific immunomodulatory role(s) Fc[varepsilon]RI-expressing pDC, and other Fc[varepsilon]RI-expressing antigen presenting cells, may play in IgE-mediated immune reactions in vivo.