ON THE COVER
Janardhan et al. demonstrate endothelial KRAS or BRAF gain of-function mutations as a causal mechanism for hepatic vascular cavernomas. The image shows Lyve1 (green), Pecam1 (red), and Hoechst (blue) coimmunofluorescent stained liver sections with cavernous sinusoids in BrafV600E F/+; Lyve1Cre embryos. Image © Janardhan et al., 2020. https://doi.org/10.1084/jem.20192205
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People & Ideas
Siamon Gordon: A half-century fascination with macrophages
Siamon Gordon: A half-century fascination with macrophages
ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease
Deciphering ZBP1 activation and its role in sterile or viral-induced cell death.
“B” aware: Memory lane access is restricted!
Understanding the molecular mechanisms that govern the differentiation of high-affinity germinal center (GC) B cells into memory B cells (MBCs) versus plasma cells is a major quest of adaptive immunity. In this issue, Toboso-Navasa et al. provide evidence that the MYC–MIZ1 transcriptional repressor complex restricts the differentiation of GC B cells into MBCs.
Brief Definitive Reports
Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation
Devos et al. find that the recognition of endogenous nucleic acids by the nucleic acid sensor ZBP1 causes necroptosis of RIPK1-deficient keratinocytes. This process drives the development of an inflammatory skin disease characterized by an IL-17 immune response.
Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir
Mendoza et al. identify clones of HIV-1 defective or intact latent proviruses within antigen-responsive CD4+ T cells. This study suggests that exposure to chronic or recurrent antigens may contribute to reservoir persistence by stimulating the clonal expansion of latently infected CD4+ T cells.
Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells
CMV is emerging as a key driver of immunosenescence. Bowyer et al. report that an expansion of phenotypically senescent CD4+ and CD8+ T cells is associated with reduced responses to Ebola vaccines ChAd3–EBO-Z and MVA–EBO-Z in young UK and Senegalese adults.
The endothelial basement membrane acts as a checkpoint for entry of pathogenic T cells into the brain
Zhang et al. identify a new subendothelial/basement membrane (BM) niche in which the phenotype of CNS-infiltrating T cells is modulated by interaction with endothelial BM laminins via integrins α6β1 and αvβ1, affecting differentiation to pathogenic Th17 cells and motility.
NLRC4 inflammasome activation is NLRP3- and phosphorylation-independent during infection and does not protect from melanoma
Clarifying conflicting previous reports, Tenthorey et al. demonstrate, in vitro and in vivo, that phosphorylation of NLRC4 is neither necessary nor sufficient for NAIP/NLRC4 inflammasome activation. Further, NLRC4 plays no role in a model of melanoma.
Technical Advances and Resources
Efficient gene knockout in primary human and murine myeloid cells by non-viral delivery of CRISPR-Cas9
Highly efficient gene editing in primary myeloid cells is made possible by optimized non-viral delivery of CRISPR-Cas9. This enables single and multiplexed gene knockout in monocytes, macrophages, and dendritic cells to advance innate immunity research and cell therapy.
HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Bodda et al. show that the deubiquitinase activity of the HSV1 VP1-2 protein inhibits induction of type I interferon in the brain. This is mediated through deubiquitination of the signaling protein STING, thus preventing activation of host defense after sensing of viral DNA by cGAS.
TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination
Ubiquitination is an essential mechanism in controlling antiviral immunity. Zhu et al. identify TRIM24 as a critical regulator for defending RNA virus infection through ubiquitinating TRAF3 and show that virus-activated IRF3 suppresses TRIM24 expression, forming a negative feedback loop to restrain overactivation of antiviral signaling.
Restriction of memory B cell differentiation at the germinal center B cell positive selection stage
Germinal center (GC) positively selected B cells are primarily fated for GC expansion and plasma cell formation. This study reveals that memory B cell differentiation is restricted in positively selected B cells by the MYC–MIZ1 transcriptional repressor complex.
Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung
The transcriptional repressor Blimp-1, known to constrain autoimmunity, is an unexpected and critical positive regulator of Th2 cells in the lung acting via an IL-10–STAT3 axis in response to inhaled allergens, driving pathophysiology associated with asthma disease.
Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells
Tay et al. show that HDAC3 acts early during CD8 T cell activation to inhibit cytotoxicity and effector differentiation gene programs. This study identifies a novel role for HDAC3 as an epigenetic regulator of CD8 T cell cytotoxicity and persistence following activation.
Impact of checkpoint blockade on cancer vaccine–activated CD8+ T cell responses
Santos et al. analyze cancer patient vaccine antigen-specific T cells for the importance of immune checkpoint molecule and gene pathway expression. CTLA-4 and PD-1 pathways are significantly correlated to T cell response and clinical outcomes, and sequence of pathway blockade is critical.
SIRT1–NOX4 signaling axis regulates cancer cachexia
This study demonstrates a novel signaling pathway regulating pancreatic cancer cachexia. These results establish that the Sirt1–Nox4 signaling axis plays an essential role in the manifestation of pancreatic cancer cachexia, and inhibition of this axis abrogates the cachexia syndrome.
KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition
This study demonstrates endothelial KRAS or BRAF gain-of-function mutations as a causal mechanism for hepatic vascular cavernomas, the most common benign tumor of the liver. RAS-MAPK1 signaling inhibition rescues hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice.
Correction: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome