ON THE COVER
Rodero et al. use single molecule arrays combined with high-affinity autoantibodies from APECED patients to detect clinically relevant attomolar concentrations of interferon-alpha in different human diseases. This permits the first direct assay of interferon-alpha in patient samples since its initial discovery 60 years ago in the seminal study of Isaacs and Lindenmann. Scanning electron micrograph of a femtoliter-volume well array (gray/purple) containing beads capable of binding single molecules (shown here in green). See page 1547
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In this issue of JEM, Fu et al. identified the kinase Mink1 as a novel negative regulator of Th17 cell generation. Mink1, activated by reactive oxygen species (ROS), prevents TGF-β activation of Smad2, therefore limiting Th17 cell differentiation.
In this issue, Deniset et al. provide new data that extend our knowledge on the mechanisms whereby Streptococcus pneumoniae is cleared by the spleen. The authors identify novel populations of murine splenic neutrophils that localize in the red pulp and the marginal zone. During the acute phases of S. pneumoniae infection, these populations of splenic neutrophils act in concert with specialized macrophage and B cell populations to provide very rapid innate immune protection.
Faria et al. discuss the concept that immune cells undergo specialized adaptation to tissue-specific conditions and its potential implications for tolerance and immunity.
Brief Definitive Report
Ising et al. report expression of anti-tau scFvs in the brain of a mouse model of tauopathy by AAV-mediated gene transfer. Treated mice show markedly decreased tau hyperphosphorylation and detergent-soluble tau species. Therefore, the Fc domain is not required to mediate effects in tauopathy.
In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein
Deeg et al. show a novel line of transgenic mice expressing restriction factor MxA exhibits robust resistance to influenza viruses of avian but not human origin. In vivo evasion of MxA is mediated by distinct amino acids in the nucleoprotein of human influenza viruses.
Reber et al. reveal a protective function for neutrophils after lethal endotoxin challenge using a novel mouse model of diphtheria toxin–inducible neutropenia. Neutrophil expression of myeloperoxidase (MPO) is necessary for this protection. These findings imply that neutrophils protect the host by limiting the extent of LPS-induced pathology in an MPO-dependent manner.
Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells
Kräutler et al. show that differentiation of antibody-producing plasma cells from germinal center (GC) B cell precursors is initiated by direct contact with high-affinity antigen within the GC but completed by separate signals delivered by collaborating, GC-resident T follicular helper cells.
Schweighoffer et al. demonstrate that in B cells, TLR4 transduces signals through two distinct pathways: one via the BCR to the activation of SYK, ERK, and AKT and the other via MYD88 to the activation of NF-κB.
Macrophages are important for tissue function, and adapt phenotypically to each tissue by factors produced locally. A-Gonzalez et al. now show that phagocytosis of unwanted cells additionally contributes to imprinting macrophage heterogeneity, thus promoting tissue homeostasis.
TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects
Many pathogenic bacterial species produce spores, which may play an important role in their interaction with the host. Choo et al. show that the spores of Bacillus anthracis, the etiologic agent of anthrax, induce type I IFN signaling and disrupt host immune defense via TLR-stimulating RNA.
BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection
Kitada et al. demonstrate that transcription factor BATF2 induced by IFN-γ in macrophages and dendritic cells prevents Th17-mediated multiorgan pathology through suppression of IL-23 production during T. cruzi infection.
The spleen is integral for protection against encapsulated bacteria. Using intravital imaging, Deniset et al. demonstrate that resident neutrophil and macrophage populations in the spleen coordinate the rapid clearance of Streptococcus pneumoniae, ensuring sufficient time for subseqent protective antibody production.
Lysophosphatidylcholine is associated with neurodegeneration and demyelination. Freeman et al. demonstrate that lysophosphatidylcholine triggers NLRP3- and NLRC4-dependent inflammasome activation, and in a synergistic fashion, NLRP3 and NLRC4 contribute to a cuprizone-induced demyelination model in vivo.
Enteropathy-associated T cell lymphoma (EATL) is the most common oncologic complication of celiac disease. Moffitt and colleagues identify novel EATL-defining mutations in SETD2, as well as clinically relevant mutations in the JAK-STAT pathway.
Hepatocellular cancers arise in a background of liver damage and inflammation. Bakiri et al. describe the function of the transcription factor c-Fos/AP-1 using mouse models and human data. c-Fos affects cholesterol and bile acid metabolism and induces DNA damage and inflammation, thus promoting liver cancer.
Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries
Sun et al. demonstrate that STAT3 signaling is important for reactive astrocyte remodeling within the injured optic nerve head. Importantly, this reactivity preserves visual function after various optic nerve injuries, including experimental glaucoma.
Cohesin is associated with the developmental disorder Cornelia de Lange syndrome. Fujita et al. show that low levels of cohesin expression in the developing brain result in changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype.
Fu et al. demonstrate that reactive oxygen species (ROS)–sensing molecule misshapen/NIK-related kinase 1 (MINK1) can specifically suppress Th 17 cell differentiation through direct phosphorylation of SMAD2. This study provides the mechanism of how ROS limit inflammatory response and unveils the potential health risk of antioxidant supplementation.
Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs
Ma and colleagues identify CXXC5 as an epigenetic regulator required for maintaining the hypomethylation of a subset of CGIs, thereby promoting the expression of transcriptional factors such as IRF7 in pDCs to enable robust IFN response to viral infection.
The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity
Xiao et al. demonstrate that a protein kinase, TBK1, regulates the function of dendritic cells in mediating immune responses.
Lehmann et al. targeted antigens to Fcγ receptors expressed on various antigen-presenting cells. Induced CD4+ and CD8+ T cell responses were solely dependent on CD11b+ and CD8+ DC subsets, respectively, but independent of receptor intrinsic ITAM or ITIM signaling domains.
TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand
T follicular helper cells (Tfh) are implicated in various pathological conditions, but how they differentiate in Th2-skewed environments is unknown. Pattarini et al. delineate a pathway for human Tfh differentiation induced by TSLP through OX40L, relevant to atopic dermatitis.
Technical Advances and Resources
Rodero et al. report the direct quantification of IFNα protein in monogenic interferonopathies, autoimmunity, and infectious disease states, made possible by the combination of digital ELISA and high-affinity autoantibodies isolated from APECED patients, revealing differential levels and cellular sources dependent on underlying pathology.
Correction: The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells