May 2017 | Volume 214, No. 5
- MINK1: The missing link between ROS and its inhibition of Th17 cells
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.
- Location in the spleen dictates the function of murine neutrophils
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.
- Tissue adaptation: Implications for gut immunity and tolerance
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 Reports
- AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy
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.
- Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide
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.
- TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK
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.
- Phagocytosis imprints heterogeneity in tissue-resident macrophages
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.
- Splenic Ly6Ghigh mature and Ly6Gint immature neutrophils contribute to eradication of S. pneumoniae
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.
- NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes
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 subtypes are characterized by loss of function of SETD2
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.
- Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation
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.
- Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior
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.
- Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1
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.
- DC subset–specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo
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.
- Detection of interferon alpha protein reveals differential levels and cellular sources in disease
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.