Immunity
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Toll-like receptors (TLRs) play prominent roles in initiating immune responses to infection, but their roles in particular cell types in vivo are not established. Here we report the generation of mice selectively lacking the crucial TLR-signaling adaptor MyD88 in dendritic cells (DCs). ⋯ Whereas the innate interferon-gamma response of natural killer cells and of natural killer T cells and the Th1 polarization of antigen-specific CD4(+) T cells were severely compromised after treatment with a soluble TLR9 ligand, they were largely intact after administration of an aggregated TLR9 ligand. These results demonstrate that the physical form of a TLR ligand affects which cells can respond to it and that DCs and other innate immune cells can respond via TLRs and collaborate in promoting Th1 adaptive immune responses to an aggregated stimulus.
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In this issue of Immunity, Hou et al. (2008) describe the generation of mice that selectively lack the adaptor protein MyD88 in dendritic cells (DCs). These mice demonstrate that the requirement for Toll-like receptor (TLR) signaling in DCs is dependent on the physical form of the TLR ligand.
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Comparative Study
Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis.
Anaphylaxis is an acute, severe, and potentially fatal systemic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pathway mediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. ⋯ Upon capture of IgG-allergen complexes, basophils released platelet-activating factor (PAF), leading to increased vascular permeability. These results highlight a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systemic anaphylaxis: one mediated by basophils, IgG, and PAF and the other "classical" pathway mediated by mast cells, IgE, and histamine.
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Secretion of the proinflammatory cytokine IL-1beta requires caspase-1 and Toll-like receptor (TLR) signaling. However, Kanneganti et al. (2007) find that bacteria can use pore-forming mechanisms to activate caspase-1 for the production of IL-1beta precursor independently of TLRs.
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CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.
The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient COS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. ⋯ Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.