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The type I interferon (IFNα) response is crucial for viral clearance during primary viral infections. Plasmacytoid dendritic cells are important early responders during systemic viral infections and, in some cases, the sole producers of IFNα. However, their role in IFNα production during memory responses is unclear. We found that IFNα production is absent during a murine viral memory response despite colocalization of virus and pDCs to the splenic marginal zone. The absence of interferon was dependent on circulating antibody, and reversed by the transgenic expression of the activating human FcγRIIA receptor on pDCs. Furthermore, FcγRIIB was required for Sendai Virus immune complex (SeV IC) uptake by splenic pDCs in vitro and internalization via FcγRIIb prevented cargo from accessing TLR signaling endosomes. Thus, pDCs bind viral immune complexes via FcγRIIB, and prevent IFNα production in vivo during viral memory responses. This antibody-dependent, IFNα regulation maybe an important mechanism by which the potentially deleterious effects of IFNα are prevented during a secondary infection.

The pattern recognition receptor, RAGE, has been shown to be involved in adaptive immune responses but its role on the components of these responses is not well understood. We have studied the effects of a small molecule inhibitor of RAGE and the deletion of the receptor (RAGE-/- mice) on T cell responses involved in autoimmunity and allograft rejection. Syngeneic islet graft and islet allograft rejection was reduced in NOD and B6 mice treated with TTP488, a small molecule RAGE inhibitor (p0.001). RAGE-/- mice with streptozotocin-induced diabetes showed delayed rejection of islet allografts compared with wild type (WT) mice (p0.02). This response in vivo correlated with reduced proliferative responses of RAGE-/- T cells in MLRs and in WT T cells cultured with TTP488. Overall T cell proliferation following activation with anti-CD3 and anti-CD28 mAbs were similar in RAGE-/- and WT cells, but RAGE-/- T cells did not respond to costimulation with anti-CD28 mAb. Furthermore, culture supernatants from cultures with anti-CD3 and anti-CD28 mAbs showed higher levels of IL-10, IL-5, and TNF-alpha with RAGE-/- compared with WT T cells, and WT T cells showed reduced production of IFN-gamma in the presence of TTP488, suggesting that RAGE may be important in the differentiation of T cell subjects. Indeed, by real-time PCR, we found higher levels of RAGE mRNA expression on clonal T cells activated under Th1 differentiating conditions. We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1(+) T cells.