ON THE COVER
Diny et al. report that eosinophils mediate progression of myocarditis to inflammatory dilated cardiomyopathy through interleukin-4 in a mouse model of autoimmune myocarditis. The electron micrograph is taken from the heart of a hypereosinophilic mouse with acute myocarditis and shows eosinophils (orange) and other immune cells (yellow) in blood vessels (green) and infiltrating between cardiomyocytes (blue). See page 943
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A long-lived latent reservoir for HIV-1 persists in CD4+ T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.
Quach and Quintana-Murci review the genetic and evolutionary history of our species, including how natural selection has shaped human genome diversity, and discuss the added value of population and functional genomic approaches in settings relevant to immunity and infection.
Brief Definitive Report
PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity
Both tumor- and host-derived PD-L1 can play critical roles in immunosuppression; differences in tumor immunogenicity appear to underlie their relative contributions. Juneja et al. show that in immunogenic MC38 tumors, PD-L1 on tumor cells dominates in suppressing tumor immunity by inhibiting CD8 T cell cytotoxicity.
Using in vivo experimentation and an in vitro microfluidic system, Wolf et al. demonstrate that monocytes require low levels of self-made TNF for their survival, both during monopoiesis and under specific immune challenges. They highlight the significance of this autonomous mechanism in a mouse multiple sclerosis model in which TNF-deficient monocytes survive less in the inflamed spinal cord, resulting in delayed disease onset.
Fu et al. show that ZMPSTE24 is a broad-spectrum antiviral protein that inhibits entry of selected fusogenic viruses by functioning as an effector in the IFITM pathway. ZMPSTE24 protease activity is dispensable for viral restriction. In mice, ZMPSTE24 deficiency increases susceptibility to influenza infection.
Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
Getahun et al. show that the inositol phosphatase PTEN plays a role in the inhibition of B cell functions observed during acute viral infections.
Diny et al. report a pathogenic role for eosinophils in autoimmune myocarditis and dilated cardiomyopathy. Eosinophils are required for progression of myocarditis to dilated cardiomyopathy and drive severe disease when present in large numbers. Activated cardiac eosinophils mediate this process through IL-4.
Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics
The latent reservoir for HIV-1 in resting CD4+ T cells prevents cure with antiretroviral therapy. Hosmane et al. provide evidence supporting the hypothesis that a larger fraction of cells in the reservoir is generated by cell proliferation than by direct infection.
Hu et al. show that sumoylation of the viral RNA sensors RIG-I and MDA5 by TRIM38 in uninfected and early-infected cells, and their desumoylation by SENP2 in the late phase of infection, ensure efficient innate immune responses to RNA viruses and their timely termination upon resolution of infection.
p38 inhibition provides anti–DNA virus immunity by regulation of USP21 phosphorylation and STING activation
Chen et al. show that USP21 is a deubiquitinating enzyme for the adaptor protein STING and that it negatively regulates the DNA virus–induced production of type I interferons. HSV-1 infection recruited USP21 to STING at a late stage by p38-mediated phosphorylation of USP21 at Ser538.
Blaser et al. use live imaging of the zebrafish hematopoietic niche to show that cxcl8/cxcr1 signaling positively regulates HSPC engraftment by increasing HSPC-niche interactions, HSPC mitotic rate, niche size, and expression of cxcl12a in a niche-autonomous manner.
LeBlanc et al. uncover secretogranin III (Scg3) as a unique disease-associated vascular permeability and angiogenic factor using comparative ligandomics. Scg3-neutralizing antibodies alleviate vascular leakage in diabetic retinopathy mice and retinal neovascularization in oxygen-induced retinopathy mice with high efficacy.
Fantin et al. show that the VEGF isoform VEGF165 signals through a complex of VEGFR2 and NRP1, in which the NRP1 cytoplasmic domain promotes the ABL-mediated activation of SRC family kinases to evoke a hyperpermeability response, a known cause of pathological edema.
AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program
The treatment of BLBC represents an unmet medical need. Wu et al. show that AKR1B1 facilitates BLBC progression through a positive feedback loop that activates the EMT program, suggesting that inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC.
Czirr et al. report that microglia lacking complement receptor 3 display increased extracellular Aβ degrading activity and that targeting the receptor with a small molecule increases Aβ clearance in vivo, thus identifying a microglial receptor as a novel therapeutic target.
Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation
Li et al. show that OGT-mediated STAT3 O-GlcNAcylation, which is modulated by CUL3-Nrf2 signaling, negatively regulates STAT3 phosphorylation and IL-10 production in macrophages and exacerbates experimental colitis and colitis-associated cancer.
Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity
Thomas et al. show that a novel protein, Eros, controls the abundance of components of the phagocyte NADPH oxidase, making it essential for the phagocyte respiratory burst and defense against common infections.
Takahashi et al. find that epithelial cell–conditional knockdown of transcription factor Fli1 in mice drives systemic autoimmunity derived from thymic defects as well as selective tissue fibrosis in the skin and esophagus, mimicking human scleroderma. This study unravels the unanswered question about the origin of autoimmunity and selective tissue fibrosis in this disease.
Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection
Although type I interferon is critical for NK cell activation, the underlying mechanism is under debate and is unknown during a mucosal infection. Lee et al. have determined that type I interferon induces inflammatory monocytes to produce IL-18 to directly activate NK cells to combat viral infections.
Pms2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs
Girelli Zubani et al. show that the Pms2 component of the mismatch repair complex and multiple uracil glycosylases contribute, each with a distinct strand bias, to enlarge the Ig gene mutation spectrum from G-C to A-T bases.
The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help
Inoue et al. show that Foxo1 controls not only GC polarization but also GC B cell proliferation, the latter of which is mediated by Foxo1-dependent BATF up-regulation.