ON THE COVER
Brummelman et al. identify partially exhausted CD8+ T cells with enhanced stem-like properties and cytotoxicity infiltrating human solid tumors. The cover is a color-coded heat map depicting clusters identified by Phenograph in samples from lung cancer patients. The image was taken from the original manuscript and modified by the JEM editorial office. See page 2520.
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Found in Translation
Chris Boshoff, Senior Vice President of Immuno-Oncology, Translational and Early Development at Pfizer, and colleagues Samra Turajlic and Charles Swanton from the Francis Crick Institute and University College London give us their personal point of view on new insights and future therapeutic approaches for renal cancer.
In this issue of JEM, Singhal et al. explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair.
In this issue of JEM, Fistonich et al. address how the bone marrow microenvironment supports diverse lineages through multiple developmental stages. Differential motility between pro- and preB cells results in differential IL-7 exposure, and, intriguingly, stromal cells respond to abnormal B cells by reducing Il7.
Brief Definitive Report
B cell–intrinsic expression of activated PIK3CD (aPIK3CD) restricts immature BM B cell development while promoting the expansion of MZ and B1a B cells via enhanced survival. aPIK3CD is counter-productive during both T cell–independent and –dependent responses, limiting antigen-specific antibodies and class-switch recombination.
Employing a broad array of genetic lineage–tracing protocols including parabiotic pairs, Singhal et al. reveal that the fitness of liver endothelial cells (ECs) determines whether resident ECs or bone marrow–derived mononuclear cells will be adopted for vascular regeneration.
Tanaka et al. show that Sox12, a member of SoxC family, is induced by TCR-NFAT signaling in T cells, binds to the Foxp3 promoter and drives its transcription, and induces the differentiation of T reg cells in the periphery during colitis.
High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors
CD8+ T cells infiltrating tumors are largely dysfunctional. Brummelman and Mazza et al. identify partially exhausted CXCR5+ TIM-3– CD8+ T cells with enhanced stem-like properties and cytotoxicity infiltrating human solid tumors. These cells express candidate immunotherapeutic targets (PD-1, TIGIT and CD27) for their reinvigoration.
Loyher et al. demonstrate that lung tumors are densely colonized by macrophages of various ontogenies. These distinct developmental origins dictate tumor-associated macrophages relative anatomical distributions, functions and responses to anti-cancer therapies.
Nestor et al. examine how lupus antibodies that enter the brain cause neuronal dysfunction and cognitive impairment. The results show that activated microglia are critical for neuronal damage and that inhibiting them can preserve neuronal function and cognition.
We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced.
Cell circuits between B cell progenitors and IL-7+ mesenchymal progenitor cells control B cell development
B cell development is characterized by well-defined transitions. Fistonich et al. demonstrate that two distinct cell circuits formed between proB, preB, and IL-7+ cells regulate the size and quality of B cell progenitors and control B cell development.
Yang et al. show that NGLY1, a deglycosylation enzyme, regulates mitochondrial homeostasis and mitophagy through transcription factor NRF1. In the absence of NGLY1, cellular clearance of damaged mitochondria by mitophagy is impaired, resulting in chronic activation of innate immune nucleic acid–sensing pathways.
Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity
Spontaneous CLIP dissociation from an autoimmunity-associated MHC II protein enhances presentation of peptides released by insulin-producing β cells. Presentation of such extracellular peptides does not require endosomal antigen processing and augments islet infiltration by CD4 T cells.
Intracerebral hemorrhage is a devastating neurological injury that produces poor patient outcomes. In this report, Vaibhav et al. demonstrate that remote ischemic post-conditioning noninvasively accelerates hematoma resolution by enhancing AMPK-dependent alternative macrophage activation.
Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation
Atherosclerosis preferentially develops in areas of disturbed flow. Albarrán-Juárez et al. provide evidence that this depends on at least two different endothelial mechanosignaling pathways, a flow direction-independent pathway involving Piezo1 and Gq/G11, as well as integrin signaling, which is only initiated in response to disturbed flow.
Adenoid cystic carcinoma (ACC) is a salivary gland malignancy that has no effective therapy and is caused by translocations involving MYB. A zebrafish chemical genetic screen identifies the retinoic acid class of compounds as potential MYB-inhibitory agents. Preclinical ACC mouse xenotransplantation models confirm the in vivo efficacy of retinoic acid, which represents a potential therapy for ACC.
Technical Advances and Resources
One-step generation of monoclonal B cell receptor mice capable of isotype switching and somatic hypermutation
Jacobsen et al. describe a method to quickly generate mice carrying monoclonal immunoglobulins using CRISPR–Cas9-based genome editing in zygotes. Both chains are targeted in tandem into the Igh locus, allowing for isotype switching, somatic hypermutation, and affinity maturation.