Frontiers in immunology
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Frontiers in immunology · Jan 2019
Establishment and Maintenance of Conventional and Circulation-Driven Lung-Resident Memory CD8+ T Cells Following Respiratory Virus Infections.
Antigen-specific CD8+ tissue-resident memory T cells (TRM cells) persist in the lung following resolution of a respiratory virus infection and provide first-line defense against reinfection. In contrast to other memory T cell populations, such as central memory T cells that circulate between lymph and blood, and effector memory T cells (TEM cells) that circulate between blood and peripheral tissues, TRM cells are best defined by their permanent residency in the tissues and their independence from circulatory T cell populations. Consistent with this, we recently demonstrated that CD8+ TRM cells primarily reside within specific niches in the lung (Repair-Associated Memory Depots; RAMD) that normally exclude CD8+ TEM cells. ⋯ Here we propose a model in which the majority of CD8+ TRM cells are maintained within RAMD (conventional TRM) whereas a small fraction of TRM are derived from circulating CD8+ TEM cells and maintained in the interstitium. The numbers of both types of TRM cells wane over time due to declines in both RAMD availability and the overall number of TEM in the circulation. This model is consistent with most published reports and has important implications for the development of vaccines designed to elicit protective T cell memory in the lung.
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Frontiers in immunology · Jan 2019
Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor α7 Subunit (α7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis.
Sepsis is one of the leading causes of death in hospitalized patients and the chronic and low-grade inflammation observed in obesity seems to worsen susceptibility and morbidity of infections. However, little is known with respect to a short-term high-fat diet (HFD) and its role in the development of sepsis. Here, we show for the first time, that short-term HFD consumption impairs early nicotinic acetylcholine receptor α7 subunit (α7nAChR)- mediated signaling, one of the major components of the cholinergic anti-inflammatory pathway, with a focus on hypothalamic inflammation and innate immune response. ⋯ Moreover, PNU-282987 administration (i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS injection. Nevertheless, when the i.c.v. injection of PNU-282987 was performed the anti-inflammatory effect was much smaller in HFD-fed mice than SC-fed mice. Here, we provide evidence that a short-term HFD impairs early α7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis.
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Frontiers in immunology · Jan 2019
Meta AnalysisRisk of Pneumonitis and Pneumonia Associated With Immune Checkpoint Inhibitors for Solid Tumors: A Systematic Review and Meta-Analysis.
Background: We performed a systematic review and meta-analysis to evaluate the risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods: The following keywords were used in searching the Embase and PubMed database: pneumonitis, pneumonia, and immune checkpoint inhibitors. The data was analyzed by using the R software and Metafor package. ⋯ Conclusions: PD-1/PD-L1 inhibitors treatment could increase the risk of all-grade pneumonitis. CTLA4 inhibitor ipilimumab treatment alone could not increase the risk of pneumonitis but could augment the risk of pneumonitis in PD-1/PD-L1 inhibitor treated patients. There was no significant increase in the risk of pneumonia after either PD-1/PDL-1inhibitor or CTLA4 inhibitor treatment alone or in combination.
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Frontiers in immunology · Jan 2019
ReviewImmunopathogenesis of Immune Checkpoint Inhibitor-Related Adverse Events: Roles of the Intestinal Microbiome and Th17 Cells.
The advent of novel, innovative, and effective anti-cancer immunotherapies has engendered an era of renewed optimism among cancer specialists and their patients. Foremost among these successful immunotherapies are monoclonal antibodies (MAbs) which target immune checkpoint inhibitor (ICI) molecules, most prominently cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein-1 (PD-1) and its major ligand, PD-L1. These immunotherapeutic agents are, however, often associated with the occurrence of immune-mediated toxicities known as immune-related adverse events (IRAEs). ⋯ Nevertheless, this challenge may not be insurmountable. This contention is based on acquisition of recent insights into the role of the gut microbiome and its products as determinants of the efficacy of ICI-targeted immunotherapy, as well as an increasing realization of the enigmatic involvement of Th17 cells in both anti-tumor activity and the pathogenesis of some types of IRAEs. Evidence linking the beneficial and harmful activities of ICI-targeted immunotherapy, recent mechanistic insights focusing on the gut microbiome and Th17 cells, as well as strategies to attenuate IRAEs in the setting of retention of therapeutic activity, therefore represent the major thrusts of this review.
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Frontiers in immunology · Jan 2019
Multicenter Study Clinical TrialTraumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation.
Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly understood. Here, we analyzed pre-hospital blood samples acquired from 62 adult trauma patients (mean age 44 years, range 19-95 years) within 1 h of injury (mean time to sample 39 min, range 13-59 min). ⋯ Indeed, activation of AMPK via treatment with the AMP-mimetic AICAR significantly reduced neutrophil lactate production in response to PMA stimulation, a phenomenon that we also observed for neutrophils pre-treated with mtDAMPs. Furthermore, the impairment in NET generation induced by mtDAMPs was partially ameliorated by pre-treating neutrophils with the AMPK inhibitor compound C. Taken together, our data demonstrate an immediate trauma-induced impairment in neutrophil anti-microbial function and identify mtDAMP release as a potential initiator of acute post-injury neutrophil dysfunction.