Science Immunology

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EISSN : 24709468
Total articles ≅ 332
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Dhiren F. Patel, Teresa Peiró, Nicoletta Bruno, Juho Vuononvirta, Samia Akthar, Franz Puttur, Chloe J. Pyle, Kornelija Suveizdytė, Simone A. Walker, Aran Singanayagam, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aax7006

Abstract:Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.
Chang Gon Kim, Mi Jang, Youngun Kim, Galam Leem, Kyung Hwan Kim, Hoyoung Lee, Tae-Shin Kim, Seong Jin Choi, Hyung-Don Kim, Ji Won Han, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aay0555

Abstract:Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade–resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.
Megan Sykes, David H. Sachs
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aau6298

Abstract:The success of organ transplantation is limited by the complications of immunosuppression, by chronic rejection, and by the insufficient organ supply, and thousands of patients die every year while waiting for a transplant. With recent progress in xenotransplantation permitting porcine organ graft survival of months or even years in nonhuman primates, there is renewed interest in its potential to alleviate the organ shortage. Many of these advances are the result of our heightened capacity to modify pigs genetically, particularly with the development of CRISPR-Cas9–based gene editing methodologies. Although this approach allows the engineering of pig organs that are less prone to rejection, the clinical application of xenotransplantation will require the ability to avoid the ravages of a multifaceted attack on the immune system while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. In this review, we will discuss the potential and limitations of these modifications and how the engineering of the graft can be leveraged to alter the host immune response so that all types of immune attack are avoided.
Lauren E. Higdon, Jonathan S. Maltzman
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aaz9474

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Duane R. Wesemann
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aaz4195

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Velislava N. Petrova, Bevan Sawatsky, Alvin X. Han, Brigitta M. Laksono, Lisa Walz, Edyth Parker, Kathrin Pieper, Carl A. Anderson, Rory D. De Vries, Antonio Lanzavecchia, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aay6125

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SangJoon Lee, Akari Ishitsuka, Masayuki Noguchi, Mikako Hirohama, Yuji Fujiyasu, Philipp P. Petric, Martin Schwemmle, Peter Staeheli, Kyosuke Nagata, Atsushi Kawaguchi
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aau4643

Abstract:The respiratory epithelium is exposed to the environment and initiates inflammatory responses to exclude pathogens. Influenza A virus (IAV) infection triggers inflammatory responses in the respiratory mucosa, but the mechanisms of inflammasome activation are poorly understood. We identified MxA as a functional inflammasome sensor in respiratory epithelial cells that recognizes IAV nucleoprotein and triggers the formation of ASC (apoptosis-associated speck-like protein containing a CARD) specks via interaction of its GTPase domain with the PYD domain of ASC. ASC specks were present in bronchiolar epithelial cells of IAV-infected MxA-transgenic mice, which correlated with early IL-1β production and early recruitment of granulocytes in the lungs of infected mice. Collectively, these results demonstrate that MxA contributes to IAV resistance by triggering a rapid inflammatory response in infected respiratory epithelial cells.
Masahiko Akamatsu, Norihisa Mikami, Naganari Ohkura, Ryoji Kawakami, Yohko Kitagawa, Atsushi Sugimoto, Keiji Hirota, Naoto Nakamura, Satoru Ujihara, Toshio Kurosaki, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aaw2707

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Sebastian Lorenz Knackstedt, Athina Georgiadou, Falko Apel, Ulrike Abu-Abed, Christopher A. Moxon, Aubrey J. Cunnington, Bärbel Raupach, Deirdre Cunningham, Jean Langhorne, Renate Krüger, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aaw0336

Abstract:Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule-1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.
Yu Si, Simon F. Merz, Philipp Jansen, Baoxiao Wang, Kirsten Bruderek, Petra Altenhoff, Stefan Mattheis, Stephan Lang, Matthias Gunzer, Joachim Klode, et al.
Science Immunology, Volume 4; doi:10.1126/sciimmunol.aaw9159

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