Issues

This comprehensive review by Villavicencio Gonzalez and Zoghbi integrates established and emerging insights into the pathogenic mechanisms of polyglutamine disorders, emphasizing recent discoveries on transcriptional dysregulation, somatic expansion, protein accumulation, and cellular toxicity. It explores evolving therapeutic strategies and recent clinical trials for these disorders.

The number of human diseases caused by genetic disruption of the interferon regulatory factors (IRFs) is growing rapidly. Here, Stojcic et al. review the biology and clinical features of inborn errors of IRFs, a group of monogenic disorders affecting the IRF family of transcription factors.

Bissett et al. demonstrate that mucosal delivery of heterologous omicron vaccine is able to overcome deleterious prime-derived immunological imprinting via multiple mechanisms, with intranasal boosting responses unaffected by suppressive prime-derived antibodies, and cross-reactive memory T cells engaged and recruited to the lungs.

This study shows that the lung-localized secondary compared with primary response to influenza infection exhibits reduced inflammatory cytokines and increased IL-10 production. Lung tissue–resident memory T cells are the predominant producers of IL-10, which reduces macrophage-mediated inflammation and promotes T cell effector function.

This study reveals how the structure and cellular morphology of human dermal afferent lymphatic vessels differ from the current, primarily mouse tissue–based textbook description. Furthermore, it identifies the new valve marker CD24 and reveals its contribution to mesenteric valve formation.

The authors found that the FCRL3 receptor is expressed upon repetitive activation of human memory T lymphocytes and limits their responses via inhibitory pathways. This study identifies FCRL3 as a regulator of highly differentiated memory T cells in humans.

Idorn et al. characterized a mouse strain harboring a mutation identified in an HSE patient. Defective IFN-driven antiviral responses led to hyperactivation of inflammatory responses, which contributed to disease development. The study identifies immunopathology as an important contributor to HSE pathogenesis.

This study reveals that the impaired IRE1α-Xbp1 pathway in gut ILC2s, caused by loss of IL-25 and rise of IFN-γ, disrupts folate-dependent one-carbon metabolism during colitis. Supplementation with one-carbon metabolism-derived AMP alleviates inflammation, suggesting a potential target of UC.

This study identifies genetically heterozygous and transcriptionally homozygous deficiency of IRF7 as an inborn error of interferon immunity underlying herpesvirus CNS infection. We find that the monoallelic expression of a deleterious IRF7 variant determines disease penetrance and exerts its effect in a spatial and temporal manner.

ADK removes adenosine to license PRMT5-mediated RIPK1 R606 symmetric dimethylation. The methylation inhibits death domain–mediated RIPK1 dimerization, which suppresses TNFα-induced cell death. ADK deficiency leads to RIPK1-driven hepatic tissue homeostasis disruption, including spontaneous liver injury in unstressed conditions and ischemia–reperfusion injury during liver surgery.

Chen et al. discover that YTHDF2 in dendritic cells negatively regulates antitumor immunity of radiotherapy. The SPI1–YTHDF2–Notch signaling–MHC-I axis orchestrates the antigen cross-presentation function of dendritic cells. Pharmacological YTHDF2 inhibition potentiates dendritic cell vaccine efficacy.

Thymic myeloid cells regulate T cell tolerance. Here, we describe their heterogeneity. We found that thymic “DC2” comprise four distinct lineages, including monocyte-derived DCs and macrophages, and conventional DC2. Among DC2, a novel population of transitional DCs, representing thymus immigrating cells, was identified.

Cinque et al. demonstrate that inhibition of a cancer-specific transcript makes human drug-tolerant persister cells visible to the immune system and re-sensitizes cancer cells to immune checkpoint blockade.

Tam et al. identify GPR34 as a splenic cDC1 receptor that is required for efferocytosis and for the cross-presentation of apoptotic cell–associated antigen to CD8 T cells. The lysophosphatidylserine-generating enzyme PLA1A acts in the GPR34 pathway to support this response.

AC corpses can be taken up by certain types of dendritic cell (DC), which cross-present dead cell–derived antigens. Tam et al. reveal that GPR34, a lysophosphatidylserine receptor, promotes AC uptake and cross-presentation by type 1 DCs (cDC1s).