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Sander LE Davis MJ Boekschoten MV Amsen D Dascher CC Ryffel B Swanson JA Müller M Blander JM 《Nature》2011,474(7351):385-389
Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines. 相似文献
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Miriam Beer Torchinsky J. Magarian Blander 《Cellular and molecular life sciences : CMLS》2010,67(9):1407-1421
In the few years since their discovery, T helper 17 cells (TH17) have been shown to play an important role in host defense against infections, and in tissue inflammation during autoimmunity.
TH17 cells produce IL-17, IL-21, IL-10, and IL-22 cytokines, and thus have broad effects on a variety of tissues. Notably, the
requirement for the immunosuppressive cytokine TGF-β along with the pro-inflammatory cytokine IL-6 for TH17 differentiation supports the intimate relationship between the TH17 subset and FOXP3+ regulatory T cells. Here, we discuss current knowledge on effector functions and differentiation of the TH17 lineage. Furthermore, we now know of a physiological stimulus for TH17 differentiation: innate immune recognition of cells undergoing apoptosis as a direct result of infection induces unique
development of this subset. As our knowledge of TH17 and T regulatory cells grows, we are building on a new framework for the understanding of effector T cell differentiation
and the biology of CD4+ T cell adaptive immune responses. 相似文献
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Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells. This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively. The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presentation of self antigens leads to tolerance. TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination. However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection. Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptide-MHC class II complexes is controlled by TLRs in a strictly phagosome-autonomous manner. 相似文献
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