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Science Immunology

Thumbi Ndung'u, Krista L Dong, Douglas S Kwon, Bruce D Walker
A program to study HIV infection is empowering African women.
September 14, 2018: Science Immunology
Joanna R DiSpirito, David Zemmour, Deepshika Ramanan, Jun Cho, Rapolas Zilionis, Allon M Klein, Christophe Benoist, Diane Mathis
Foxp3+ CD4+ regulatory T cells (Tregs ) accumulate in certain nonlymphoid tissues, where they control diverse aspects of organ homeostasis. Populations of tissue Tregs , as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other nonlymphoid tissues. We examined the diversification of Tregs in visceral adipose tissue, skeletal muscle, and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue Treg populations resulted from layering of tissue-restricted open chromatin regions over regions already open in the spleen, the latter tagged by super-enhancers and particular histone marks...
September 14, 2018: Science Immunology
Pooja Mehta, Michael D Rosenblum
Regulatory T cells indirectly suppress ILC3-driven colitis by suppressing gut-resident macrophages in a LAG-3-dependent manner.
September 7, 2018: Science Immunology
Sarah E Henrickson
An alternate strategy is described for enumerating peripheral immune cells in health and disease by epigenetic quantitative PCR.
September 7, 2018: Science Immunology
Jared Klarquist, Alisha Chitrakar, Nathan D Pennock, Augustus M Kilgore, Trevor Blain, Connie Zheng, Thomas Danhorn, Kendra Walton, Li Jiang, Jie Sun, Christopher A Hunter, Angelo D'Alessandro, Ross M Kedl
In contrast to responses against infectious challenge, T cell responses induced via adjuvanted subunit vaccination are dependent on interleukin-27 (IL-27). We show that subunit vaccine-elicited cellular responses are also dependent on IL-15, again in contrast to the infectious response. Early expression of interferon regulatory factor 4 (IRF4) was compromised in either IL-27- or IL-15-deficient environments after vaccination but not infection. Because IRF4 facilitates metabolic support of proliferating cells via aerobic glycolysis, we expected this form of metabolic activity to be reduced in the absence of IL-27 or IL-15 signaling after vaccination...
September 7, 2018: Science Immunology
Mikael J Pittet, Christopher S Garris, Sean P Arlauckas, Ralph Weissleder
Intravital microscopic imaging can uncover fundamental aspects of immune cell behavior in real time in both healthy and pathological states. Here, we discuss approaches for single-cell imaging of adaptive and innate immune cells to explore how they migrate, communicate, and mediate regulatory or effector functions in various tissues throughout the body. We further review how intravital single-cell imaging can be used to study drug effects on immune cells.
September 7, 2018: Science Immunology
Sejal Saglani, Lisa G Gregory, Avneet K Manghera, William J Branchett, Faith Uwadiae, Lewis J Entwistle, R A Oliver, Jessica E Vasiliou, Rebekah Sherburn, Stephen Lui, F Puttur, David Vöhringer, Simone A Walker, James Buckley, Ruth Grychtol, Valentina Fainardi, Laura Denney, Adam Byrne, Erika von Mutius, Andrew Bush, Clare M Lloyd
Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata ] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+ CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary Linneg CD45+ CD90+ IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33...
September 7, 2018: Science Immunology
Samuel J Balin, Matteo Pellegrini, Eynav Klechevsky, Sohui T Won, David I Weiss, Aaron W Choi, Joshua Hakimian, Jing Lu, Maria Teresa Ochoa, Barry R Bloom, Lewis L Lanier, Steffen Stenger, Robert L Modlin
Human CD8+ cytotoxic T lymphocytes (CTLs) contribute to antimicrobial defense against intracellular pathogens through secretion of cytotoxic granule proteins granzyme B, perforin, and granulysin. However, CTLs are heterogeneous in the expression of these proteins, and the subset(s) responsible for antimicrobial activity is unclear. Studying human leprosy, we found that the subset of CTLs coexpressing all three cytotoxic molecules is increased in the resistant form of the disease, can be expanded by interleukin-15 (IL-15), and is differentiated from naïve CD8+ T cells by Langerhans cells...
August 31, 2018: Science Immunology
Joseph K Rathkey, Junjie Zhao, Zhonghua Liu, Yinghua Chen, Jie Yang, Hannah C Kondolf, Bryan L Benson, Steven M Chirieleison, Alex Y Huang, George R Dubyak, Tsan S Xiao, Xiaoxia Li, Derek W Abbott
Dysregulation of inflammatory cell death is a key driver of many inflammatory diseases. Pyroptosis, a highly inflammatory form of cell death, uses intracellularly generated pores to disrupt electrolyte homeostasis and execute cell death. Gasdermin D, the pore-forming effector protein of pyroptosis, coordinates membrane lysis and the release of highly inflammatory molecules, such as interleukin-1β, which potentiate the overactivation of the innate immune response. However, to date, there is no pharmacologic mechanism to disrupt pyroptosis...
August 24, 2018: Science Immunology
Gabriel Sollberger, Axel Choidas, Garth Lawrence Burn, Peter Habenberger, Raffaella Di Lucrezia, Susanne Kordes, Sascha Menninger, Jan Eickhoff, Peter Nussbaumer, Bert Klebl, Renate Krüger, Alf Herzig, Arturo Zychlinsky
The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis...
August 24, 2018: Science Immunology
Kaiwen W Chen, Mercedes Monteleone, Dave Boucher, Gabriel Sollberger, Divya Ramnath, Nicholas D Condon, Jessica B von Pein, Petr Broz, Matthew J Sweet, Kate Schroder
Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens. We report the unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities. We show that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria ( Salmonella Δ sifA and Citrobacter rodentium ) activates noncanonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death...
August 24, 2018: Science Immunology
Giuseppe Lofano, Matthew J Gorman, Ashraf S Yousif, Wen-Han Yu, Julie M Fox, Anne-Sophie Dugast, Margaret E Ackerman, Todd J Suscovich, Joshua Weiner, Dan Barouch, Hendrik Streeck, Susan Little, Davey Smith, Douglas Richman, Douglas Lauffenburger, Bruce D Walker, Michael S Diamond, Galit Alter
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC...
August 17, 2018: Science Immunology
Christian Perez-Shibayama, Cristina Gil-Cruz, Hung-Wei Cheng, Lucas Onder, Andrea Printz, Urs Mörbe, Mario Novkovic, Conglei Li, Constantino Lopez-Macias, Matthew B Buechler, Shannon J Turley, Matthias Mack, Charlotte Soneson, Mark D Robinson, Elke Scandella, Jennifer Gommerman, Burkhard Ludewig
Immune protection of the body cavities depends on the swift activation of innate and adaptive immune responses in nonclassical secondary lymphoid organs known as fat-associated lymphoid clusters (FALCs). Compared with classical secondary lymphoid organs such as lymph nodes and Peyer's patches, FALCs develop along distinct differentiation trajectories and display a reduced structural complexity. Although it is well established that fibroblastic reticular cells (FRCs) are an integral component of the immune-stimulating infrastructure of classical secondary lymphoid organs, the role of FRCs in FALC-dependent peritoneal immunity remains unclear...
August 10, 2018: Science Immunology
Samuel Murphy, Shiv Pillai
CD8+ T cells formed early in life respond more rapidly to infection, and this appears to be the result of a pre-programmed effector-like chromatin landscape.
August 3, 2018: Science Immunology
Rachael A Clark
Treating elderly patients with two low-dose mTOR inhibitors that selectively block TORC1 led to a decrease in infection rates.
August 3, 2018: Science Immunology
Marsha Wills-Karp
Neutrophil cytoplasts are linked to amplification of T helper 17-mediated inflammation and severe asthma.
August 3, 2018: Science Immunology
Nandini Krishnamoorthy, David N Douda, Thayse R Brüggemann, Isabell Ricklefs, Melody G Duvall, Raja-Elie E Abdulnour, Kimberly Martinod, Luciana Tavares, Xiao Wang, Manuela Cernadas, Elliot Israel, David T Mauger, Eugene R Bleecker, Mario Castro, Serpil C Erzurum, Benjamin M Gaston, Nizar N Jarjour, Sally Wenzel, Eleanor Dunican, John V Fahy, Daniel Irimia, Denisa D Wagner, Bruce D Levy
Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis...
August 3, 2018: Science Immunology
Jeremy P Snook, Chulwoo Kim, Matthew A Williams
CD4+ T cell responses are composed of heterogeneous T cell receptor (TCR) signals that influence the acquisition of effector and memory characteristics. We sought to define early TCR-dependent activation events that control T cell differentiation. A polyclonal panel of TCRs specific for the same viral antigen demonstrated substantial variability in TCR signal strength, expression of CD25, and activation of nuclear factor of activated T cells and nuclear factor κB. After viral infection, strong TCR signals corresponded to T helper cell (TH 1) differentiation, whereas T follicular helper cell and memory T cell differentiation were most efficient when TCR signals were comparatively lower...
July 20, 2018: Science Immunology
Melanie J Harriff, Curtis McMurtrey, Cara A Froyd, Haihong Jin, Meghan Cansler, Megan Null, Aneta Worley, Erin W Meermeier, Gwendolyn Swarbrick, Aaron Nilsen, Deborah A Lewinsohn, William Hildebrand, Erin J Adams, David M Lewinsohn
MR1-restricted T cells (MR1Ts) are a T cell subset that recognize and mediate host defense to a broad array of microbial pathogens, including respiratory pathogens (e.g., Mycobacterium tuberculosis , Streptococcus pyogenes , and Francisella tularensis ) and enteric pathogens (e.g., Escherichia coli and Salmonella species). Mucosal-associated invariant T (MAIT) cells, a subset of MR1Ts, were historically defined by the use of a semi-invariant T cell receptor (TCR) and recognition of small molecules derived from the riboflavin biosynthesis pathway presented on MR1...
July 13, 2018: Science Immunology
Sunil Joshi, Asha Pillai
pDC cross-presentation of antigens to CD8+ T cells depends on mitochondrial generation of reactive oxygen species.
July 6, 2018: Science Immunology
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