ON THE COVER
Thierry et al. report that IgM antibodies produced within lymph nodes in response to immunization are exported to the periphery through a peculiar network of extracellular matrix ducts known as the conduit system. The cover illustrates the transport of lymphborne fluorescent tracers (red and white) in the conduits (blue) and the lymphatic lumen of a reactive lymph node. The image was provided by the authors and modified by the JEM editorial office. See page 2972.
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Found in Translation
Ransohoff discusses why animal models have uniformly failed to predict success in neurodegenerative clinical trials.
Brief Definitive Report
IgM provides early protection against pathogens. How IgM is exported out of lymph nodes remains unknown. Thierry et al. report that B cells utilize a system of paracortical conduits to rapidly export their IgM to the periphery.
Thymic emigration is essential for establishing T cell immunity. We show the requirement for LTβR segregates from its control of medullary epithelium. Instead, our study demonstrates LTβR expression by the endothelium acts to rate limit thymocyte egress via perivascular routes.
The adult turnover mechanisms and hematopoietic origin of dendritic epidermal γδ T cells (DETCs) are poorly characterized. Gentek et al. demonstrate that DETCs originate from yolk sac hematopoiesis and clonally self-renew in the adult, akin to epidermal Langerhans cells.
The authors present a genetic mouse model for conditional depletion of γδ T cells, confirming the fetal origin and persistence of Tγδ17 cells. They show differential phenotypes after acute depletion versus constitutive γδ T cell deficiency in imiquimod-induced psoriasis.
TLRs are known to be essential for innate and adaptive immunity. Zhang et al. show the involvement of TLR8 and its endogenous ligand miR-21 in neuropathic pain via inducing ERK-dependent proinflammatory mediators’ production and neuronal hyperexcitability in the DRG.
Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies
Wang et al. demonstrate that AEP cleaves SRPK2 in tauopathies and plays a functional role in mediating tau-splicing imbalance and accelerating cognitive decline in mouse models of tauopathy.
Lane et al. demonstrate that IFNγ-induced, nonhematopoietic PD-L1 suppresses anti-melanoma immunity and identify lymphatic vessels as key mediators of response. They demonstrate that peripheral lymphatic vessels act as tissue-resident, immunological switches that balance protective immunity and tissue damage in skin.
Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer
Raz et al. demonstrate that the expression of PDGFRα distinguishes two functional CAF populations in breast tumors and lung metastases and identify a subpopulation of CAFs that are specifically recruited to the tumor microenvironment from mesenchymal stromal cells in the BM.
Mitochondrial apoptotic priming predicts response to cancer chemotherapy, but the mechanisms underlying variability in this mitochondrial phenotype among closely related tumors are poorly understood. Ariës et al. show that PRC2 loss-of-function mutations induce resistance to mitochondrial apoptosis in T-ALL.
Kras-driven non–small-cell-lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Serresi et al. show that inhibiting Ezh2 in orthotopic KrasG12D-driven NSCLC unleashes an inflammatory response rewiring tumor progression and amplifying associated vulnerabilities that could be therapeutically exploited.
These studies reveal a previously unrecognized role for Cnbp as a novel transcriptional regulator engaged downstream of innate immune receptors controlling the c-Rel–IL-12–Th1 axis, which has important implications for both host defense and inflammatory disease.
Roussel et al. identify the first patient with autosomal recessive deficiency in ICOSLG, the gene encoding the ligand for ICOS. The missense allele impairs cell surface expression of ICOSL, compromises T–B lymphocyte costimulation, and results in combined immunodeficiency.
This study demonstrates a role for the transmembrane regulator of PI3K (TrIP) in restricting early T cell activation, at least in part through effects on PI3K. It is also shown that levels of TrIP decrease preceding full T cell activation.
Zhang et al. report an essential role of the E3 ligase VHL in regulating the metabolic fitness and effector function of alveolar macrophages to prime ILC2 activation through osteopontin during pulmonary type 2 inflammation and fibrosis.
HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies
Marié et al. describe a futile cycle between constitutive histone acetyltransferases and deacetylases (HDACs) that regulates interferon-stimulated gene transcription through availability of the epigenetic reader, Brd4. Pharmacologic targeting of the HDAC/Brd4 axis resolves aberrant gene expression associated with genetic susceptibility to autoimmune interferonopathies.