People & Ideas
The Viewpoint discusses the benefits and potential limitations of using interferon lambda (IFN-λ, a type III interferon) to prevent, limit, and treat COVID-19. Due to the restricted expression of its receptor complex, IFN-λ provides localized antiviral protection to epithelial cells, including in the respiratory tract.
Antonio Bertoletti and Anthony Tanoto Tan discuss the opportunities and challenges of CAR-T cell therapy in chronic infections.
Kishimoto and colleagues present an overview of the complex biology of interleukin-6 family cytokines, focusing on signaling transduction of the receptor molecule. This review discusses the molecular mechanism of IL-6 expression and how this knowledge leads to the clinical field.
Brief Definitive Reports
Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy
Gruber et al. describe a gain-of-function mutation in STAT2 that leads to a lethal autoinflammatory disease with autosomal recessive inheritance. This syndrome defines a novel form of type I interferonopathy characterized by impaired regulation of the type I IFN response.
T cells classically express either αβ or γδ T cell receptors. We have identified T cells that express both pairs of receptors. These hybrid αβ-γδ T cells exhibit a hyperinflammatory and migratory phenotype and act as first responders in infection and CNS autoimmunity.
MDR1 is considered a dedicated drug efflux pump in tumor cells. Chen et al. show that endogenous MDR1 expression in CD8+ T cells is required for immunity to pathogens, revealing new concepts in cell-mediated immunity and informing use of MDR1 inhibitors in human cancer trials.
Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling
The gut microbiome modulates gut immunity and affects the host response to cancer immunotherapy, but how microbiota influence the tumor microenvironment remains unclear. This study reveals that some commensal gut microbiota accumulate inside the distal tumor microenvironment and facilitate CD47 blockade–mediated immunity in a STING- and interferon-dependent fashion.
USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2
USP22 is a cytoplasmic and nuclear deubiquitinating enzyme. Cai et al. show that the cytoplasmic USP22 deubiquitinates and stabilizes the importin protein KPNA2 after viral infection, which promotes nuclear translocation of IRF3 and cellular antiviral responses.
This study identifies USP22 as an essential regulator specifically for iNKT but not conventional T cell development. USP22 suppresses histone H2A monoubiquitination through its interaction with MED1 to partially control expression of genes required for iNKT cell development and differentiation.
In the present study, Louis et al. identify an inflammatory cascade mediated by IL-18 and GM-CSF–producing NK cells that promotes autoantibody-driven arthritis. GM-CSF signaling in myeloid cells is subsequently restrained by the suppressor of cytokine signaling protein CIS to prevent aberrant GM-CSF–mediated inflammation.
Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain
In this study, Bogie, Grajchen et al. show that monounsaturated fatty acids formed by stearoyl-CoA desaturase-1 impair the reparative features of macrophages and microglia in demyelinating disorders by reducing their lipid efflux capacity.
Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis
We find that pro-inflammatory activation is required for remyelination after myelin injury. We impaired inflammatory signaling and found that microglia in lesioned animals were defective in phagosome maturation, debris clearance, and also in triggering the generation of new oligodendrocytes, a process which required TNF-α.
Somatic mosaicism for MAP2K1-activating mutations causes radiographical “dripping candle wax” melorheostosis. Kang et al. report somatic mosaicism for SMAD3 mutations in bone lesions of endosteal pattern melorheostosis. The SMAD3 mutations increase TGF-β signaling and stimulate osteoblast differentiation and matrix mineralization.
Yang et al. show that IL-21 is the major extrinsic factor that inhibits the generation of IgE+ B cells under multiple conditions. IL-21, IL-4, and CD40 combinatorially regulate class switch recombination to IgE in both mouse and human B cells.
Rome et al. show that Trib1 controls effector versus exhausted T cell differentiation and function by restraining effector programming during persistent infection, revealing a new regulatory axis that could be targeted to recover waning T cell responses during chronic disease.
Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth
Francisco et al. show that chloride intracellular channel 1 (CLIC1) is an evolutionarily conserved regulator of brain tumor growth in Drosophila and medulloblastoma mouse models. CLIC1 cooperates with potassium channels to regulate cell volume homeostasis and rapid cycling of the tumor cells.
Glioma stem-like cells evade interferon suppression through MBD3/NuRD complex–mediated STAT1 downregulation
Zhan et al. reveal that glioma stem-like cells (GSCs) evade type I IFN suppression through MBD3/NuRD complex–mediated STAT1 downregulation, thereby allowing GSCs to initiate a tumor in the inhospitable microenvironment in glioblastoma (GBM).
Correction: NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS