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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.

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.

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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.

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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.

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.

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.

Technical Advances and Resources

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.

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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.

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.

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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.

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.

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.

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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.

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.

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