ON THE COVER
The two companion papers by Izawa et al. and Abolhassani et al. show that the human CD70–CD27 pathway plays a crucial role in T and B cell–mediated immunity to Epstein-Barr viral infection and associated malignancies. The image represents an abstraction of the staining of tonsils from one individual with infectious mononucleosis for CD70 (red) and the B cell marker PAX5 (brown). The image was taken from the paper by Izawa et al. and modified by the JEM editorial office.
See pages 73 and 91
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Brief Definitive Report
Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma–induced retinal pathology
Toonen et al. show that estrogen increases microglia-mediated retinal damage in neurofibromatosis-1 (Nf1) optic glioma.
Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s
von Moltke et al. demonstrate that optimal cytokine induction in group 2 innate lymphocytes results from synergy between NFAT-dependent leukotriene signaling and IL-33 signaling. This integration of signaling pathways may represent an innate substitute for the T cell receptor.
CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions
Nish et al. report that production of a fully committed Th1 effector cell occurs during an asymmetric cell division wherein the other daughter cell remains memory cell–like. Unequal transmission of metabolic signaling may be the driver of this regenerative behavior.
The cell cycle restricts activation-induced cytidine deaminase activity to early G1
Wang et al. show that antibody gene deamination by activation-induced cytidine deaminase (AID) is restricted to a short time window in early G1 as a result of AID’s transient nuclear localization and accessibility of the target sites.
Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1
Standing et al. report a novel autoinflammatory disease caused by a homozygous missense mutation in the actin-regulating protein WDR1. The disease is characterized by periodic fevers, immunodeficiency, and thrombocytopenia, with increased polymerized actin in immune cells and increased IL-18 secretion.
Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection
Izawa et al. identify the first patient with CD70 deficiency suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma. Expression of CD70 on B cells is necessary to induce proliferation of EBV-specific T cells.
Combined immunodeficiency and Epstein-Barr virus–induced B cell malignancy in humans with inherited CD70 deficiency
Abolhassani et al. show that CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of CD27 deficiency. CD70–CD27 interactions play a nonredundant role regulating humoral- and cell-mediated immunity in humans, especially for control of EBV.
Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency–induced autoimmunity via adenosine A2A receptors
He et al. show that T reg deficiency markedly induces autoimmunity and shifts gut microbiota. Remodeling microbiota by Lactobacillus reuteri was found to inhibit autoimmunity via the metabolite inosine, which interacts with the adenosine A2A receptor. This finding establishes a link between the gut microbiota, A2A receptors, and autoimmunity induced by T reg cell deficiency.
Th2 responses are primed by skin dendritic cells with distinct transcriptional profiles
Connor et al. show that transcriptomic profiling of DCs exposed to two different Th2 stimuli in vivo reveals large numbers of differentially expressed genes but few similarities between conditions.
Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
Baarsma et al. report increased expression and posttranslational modification of the noncanonical ligand WNT-5A in COPD. Fibroblast-derived WNT-5A inhibits canonical WNT–β-catenin–driven alveolar epithelial cell–mediated wound healing and transdifferentiation, and thus contributes to impaired lung regeneration and COPD pathogenesis.
Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells
Schreck et al. show that environmental Wnt5a regulates the transcriptome of HSCs during regeneration, particularly the expression of actin-regulatory mediators. In this manner, the niche affects engraftment through regulation of adhesion, migration, and homing of both normal and malignant cells.
Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE
Combining novel mouse reporters and single-cell transcriptomic analyses, Wu et al. uncover differential activation thresholds for the transcripts that direct antibody class switching to IgE versus IgG1 in response to IL-4 and explain how cell-intrinsic transcriptional heterogeneity governs CSR.
The aryl hydrocarbon receptor controls cell-fate decisions in B cells
Vaidyanathan et al. report that the environmental sensor aryl hydrocarbon receptor is inducibly expressed in B cells downstream of BCR signaling and that it controls B cell fates by negatively modulating class switching and plasma cell differentiation via aicda and prdm1, respectively.
LRCH1 interferes with DOCK8-Cdc42–induced T cell migration and ameliorates experimental autoimmune encephalomyelitis
Xu et al. show that LRCH1 interferes with the GEF activity of DOCK8 to inhibit Cdc42 activation. Upon chemokine stimulation, DOCK8 is phosphorylated and released from LRCH1 to drive cell migration. LRCH1 overexpression reduces CD4+ T cell migration to the CNS and ameliorates experimental autoimmune encephalomyelitis.
Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses
Westphal et al. demonstrate a role of lysosomal trafficking regulator Lyst that couples the regulation of endolysosomal trafficking to inflammatory responses by the control of toll-like receptor–mediated endosomal TRIF signaling pathways.
Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination
Fang et al. show that the deubiquitinase USP13 stabilizes c-Myc in glioblastoma stem cells (GSCs) by counteracting FBXL14-mediated Myc ubiquitination. c-Myc stabilization maintains GSC self-renewal and tumorigenic potential.