Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic. Given that MDSCs are a manifestation of aberrant myelopoiesis, we hypothesized that MDSCs arise from perturbations in the regulation of interferon regulatory factor–8 (IRF-8), an integral transcriptional component of myeloid differentiation and lineage commitment. Overall, we demonstrated that (a)
Jeremy D. Waight, Colleen Netherby, Mary L. Hensen, Austin Miller, Qiang Hu, Song Liu, Paul N. Bogner, Matthew R. Farren, Kelvin P. Lee, Kebin Liu, Scott I. Abrams
Recent studies described the experimental adaptation of influenza H5 HAs that confers respiratory droplet transmission (rdt) to influenza virus in ferrets. Acquisition of the ability to transmit via aerosol may lead to the development of a highly pathogenic pandemic H5 virus. Vaccines are predicted to play an important role in H5N1 control should the virus become readily transmissible between humans. We obtained PBMCs from patients who received an A/Vietnam/1203/2004 H5N1 subunit vaccine. Human hybridomas were then generated and characterized. We identified antibodies that bound the HA head domain and recognized both WT and rdt H5 HAs. We used a combination of structural techniques to define a mechanism of antibody recognition of an H5 HA receptor–binding site that neutralized H5N1 influenza viruses and pseudoviruses carrying the HA rdt variants that have mutations near the receptor-binding site. Incorporation or retention of this critical antigenic site should be considered in the design of novel H5 HA immunogens to protect against mammalian-adapted H5N1 mutants.
Natalie J. Thornburg, David P. Nannemann, David L. Blum, Jessica A. Belser, Terrence M. Tumpey, Shyam Deshpande, Gloria A. Fritz, Gopal Sapparapu, Jens C. Krause, Jeong Hyun Lee, Andrew B. Ward, David E. Lee, Sheng Li, Katie L. Winarski, Benjamin W. Spiller, Jens Meiler, James E. Crowe Jr.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within
Jennifer E. Ho, Wei-Yu Chen, Ming-Huei Chen, Martin G. Larson, Elizabeth L. McCabe, Susan Cheng, Anahita Ghorbani, Erin Coglianese, Valur Emilsson, Andrew D. Johnson, Stefan Walter, Nora Franceschini, Christopher J. O’Donnell, Abbas Dehghan, Chen Lu, Daniel Levy, Christopher Newton-Cheh, Honghuang Lin, Janine F. Felix, Eric R. Schreiter, Ramachandran S. Vasan, James L. Januzzi, Richard T. Lee, Thomas J. Wang
Antigen-specific Abs are able to enhance or suppress immune responses depending on the receptors that they bind on immune cells. Recent studies have shown that pro- or antiinflammatory effector functions of IgG Abs are also regulated through their Fc N-linked glycosylation patterns. IgG Abs that are agalactosylated (non-galactosylated) and asialylated are proinflammatory and induced by the combination of T cell–dependent (TD) protein antigens and proinflammatory costimulation. Sialylated IgG Abs, which are immunosuppressive, and Tregs are produced in the presence of TD antigens under tolerance conditions. T cell–independent (TI) B cell activation via B cell receptor (BCR) crosslinking through polysaccharides or via BCR and TLR costimulation also induces IgG Abs, but the Fc glycosylation state of these Abs is unknown. We found in mouse experiments that TI immune responses induced suppressive sialylated IgGs, in contrast to TD proinflammatory Th1 and Th17 immune responses, which induced agalactosylated and asialylated IgGs. Transfer of low amounts of antigen-specific sialylated IgG Abs was sufficient to inhibit B cell activation and pathogenic immune reactions. These findings suggest an immune regulatory function for TI immune responses through the generation of immunosuppressive sialylated IgGs and may provide insight on the role of TI immune responses during infection, vaccination, and autoimmunity.
Constanze Hess, André Winkler, Alexandra K. Lorenz, Vivien Holecska, Véronique Blanchard, Susanne Eiglmeier, Anna-Lena Schoen, Josephine Bitterling, Alexander D. Stoehr, Dominique Petzold, Tim Schommartz, Maria M.M. Mertes, Carolin T. Schoen, Ben Tiburzy, Anne Herrmann, Jörg Köhl, Rudolf A. Manz, Michael P. Madaio, Markus Berger, Hedda Wardemann, Marc Ehlers
Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.
Jean Publicover, Anuj Gaggar, Stephen Nishimura, Christine M. Van Horn, Amanda Goodsell, Marcus O. Muench, R. Lee Reinhardt, Nico van Rooijen, Adil E. Wakil, Marion Peters, Jason G. Cyster, David J. Erle, Philip Rosenthal, Stewart Cooper, Jody L. Baron
Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8+ T cells specific for MHC-I–restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivo–isolated APCs did not constitutively activate HBV-specific CD8+ T cells. However, differentiation of HBsAg+ CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells.
Adam J. Gehring, Muzlifah Haniffa, Patrick T. Kennedy, Zi Zong Ho, Carolina Boni, Amanda Shin, Nasirah Banu, Adeline Chia, Seng Gee Lim, Carlo Ferrari, Florent Ginhoux, Antonio Bertoletti
Chronic granulomatous disease (CGD) patients have recurrent life-threatening bacterial and fungal infections. Olfactomedin 4 (OLFM4) is a neutrophil granule protein that negatively regulates host defense against bacterial infection. The goal of this study was to evaluate the impact of
Wenli Liu, Ming Yan, Janyce A. Sugui, Hongzhen Li, Chengfu Xu, Jungsoo Joo, Kyung J. Kwon-Chung, William G. Coleman, Griffin P. Rodgers
TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of
Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos
Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.
Joanna M. Warszawska, Riem Gawish, Omar Sharif, Stefanie Sigel, Bianca Doninger, Karin Lakovits, Ildiko Mesteri, Manfred Nairz, Louis Boon, Alexander Spiel, Valentin Fuhrmann, Birgit Strobl, Mathias Müller, Peter Schenk, Günter Weiss, Sylvia Knapp
Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are danger-associated molecular patterns (DAMPs) generated in response to infection that can prevent the phagocytic clearance of bacteria. We investigated the mechanism underlying OxPL action in macrophages. Exposure to OxPL induced alterations in actin polymerization, resulting in spreading of peritoneal macrophages and diminished uptake of
Ulrich Matt, Omar Sharif, Rui Martins, Tanja Furtner, Lorene Langeberg, Riem Gawish, Immanuel Elbau, Ana Zivkovic, Karin Lakovits, Olga Oskolkova, Bianca Doninger, Andreas Vychytil, Thomas Perkmann, Gernot Schabbauer, Christoph J. Binder, Valery N. Bochkov, John D. Scott, Sylvia Knapp