Nature immunology
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Review
Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways.
Activation of Toll-like receptor (TLR) signaling and related pathways by microbial products drives inflammatory responses, host-defense pathways and adaptive immunity. The cost of excessive inflammation is cell and tissue damage, an underlying cause of many acute and chronic diseases. Coincident with activation of TLR signaling, a plethora of anti-inflammatory pathways and mechanisms begin to modulate inflammation until tissue repair is complete. Whereas most studies have focused on the signaling components immediately downstream of the TLRs, this Review summarizes the different levels of anti-inflammatory pathways that have evolved to abate TLR signaling and how they are integrated to prevent cell and tissue destruction.
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A vaccine against human immunodeficiency virus (HIV) seems to be on the horizon. Correlates of risk of infection for [corrected] the RV144 vaccine trial have been found. There is understanding of what makes HIV envelope-specific antibodies broadly neutralizing and new T cell vaccine approaches can overcome virus variability.
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Inflammasomes are multiprotein complexes that activate caspase-1, which leads to maturation of the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 and the induction of pyroptosis. Members of the Nod-like receptor (NLR) family, including NLRP1, NLRP3 and NLRC4, and the cytosolic receptor AIM2 are critical components of inflammasomes and link microbial and endogenous danger signals to the activation of caspase-1. In response to microbial infection, activation of the inflammasomes contributes to host protection by inducing immune responses that limit microbial invasion, but deregulated activation of inflammasomes is associated with autoinflammatory syndromes and other pathologies. Thus, understanding inflammasome pathways may provide insight into the mechanisms of host defense against microbes and the development of inflammatory disorders.
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Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. ⋯ These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.
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T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. ⋯ Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.