ON THE COVER
Tsuda et al. show that activation of the receptor for urocortin 2, Crhr2, causes cardiac dysfunction and suggest that Crhr2 blockade could be a therapeutic strategy for chronic heart failure. The cover shows an Ucn2−/− heart stained with PicroSirius red, highlighting the fibrotic area. The image was taken from the paper and modified by the JEM editorial office.
See page 1877
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Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets
Fang and Zhu discuss similarities and differences between CD4 T cell and ILC subsets and the master transcription factors that determine the heterogeneity and plasticity of these subsets.
Brief Definitive Report
Prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Tsuda et al. show that Crhr2 activation causes cardiac dysfunction and suggest Crhr2 blockade is a promising therapeutic strategy for chronic heart failure.
Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans
Fibroblast-adapted rhesus CMV–vectored vaccines protect macaques from SIV challenge and elicit unconventional CD8 T cell responses. In contrast, Murray et al. show that humans vaccinated with fibroblast-adapted human CMV vaccines generate conventional CD8 T cell responses.
Rb family proteins enforce the homeostasis of quiescent hematopoietic stem cells by repressing Socs3 expression
The mechanisms regulating the homeostasis of HSCs remain poorly understood. Here, Kim et al. identify the Rb/E2f module as a central molecular hub in the regulation of cell cycle and homeostasis in HSCs. This mechanism drives the enforced differentiation of proliferative HSCs to avoid their unnecessary accumulation.
Using stable isotope labeling, Patel et al. establish the lifespan of all three human monocyte subsets that circulate in dynamic equilibrium; in steady state, classical monocytes are short-lived precursors with the potential to become intermediate and nonclassical monocytes. They highlight that systemic inflammation induces an emergency release of classical monocytes into the circulation.
CCL21Ser is one of the ligands for chemokine receptor CCR7. Kozai et al. report that CCL21Ser is essential for the accumulation of developing thymocytes in the thymic medulla and the establishment of self-tolerance in T cells, indicating a functional inequality among CCR7 ligands in vivo.
Badran et al. demonstrate an essential contribution of biallelic RELA expression in protecting stromal and epithelial cells from TNF-mediated cell death in patients with chronic mucocutaneous ulceration.
Human MDA5 deficiency features recurrent severe human rhinovirus (HRV) infections. MDA5 serves a protective and nonredundant role in protecting against HRV in the respiratory tract, through its effects on virus sensing and triggering of antiviral IFN signaling.
Becattini et al. provide evidence that a diverse gut microbiota antagonizes the foodborne pathogen Listeria monocytogenes in the intestinal lumen, thereby reducing bloodstream invasion. Microbiota perturbation by antibiotic treatment increases susceptibility to listeriosis, with dramatic effects in immunocompromised hosts.
The human VH4-34 gene segment encodes intrinsically self-reactive antibodies that recognize I/i carbohydrates. Schickel et al. show that these self-reactive clones may represent an innate-like B cell population specialized in the containment of commensal bacteria when gut barriers are breached.
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation
Flt3 expression is absent in the large majority of phenotypic hematopoietic stem cells (HSCs). Mead et al. show that FLT3-ITD–driven myeloproliferation causes cell-extrinsic suppression of the normal HSC reservoir through disruption of HSC-supporting BM stromal cells, including overexpression of TNF.
Using a mouse model harboring a naturally occurring WHIM syndrome–linked gain-of-function Cxcr4 mutation, Freitas et al. show that Cxcr4 desensitization is critical for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors.
Solanki et al. show that stromal activity of the transcription factor Gli3 is required for B cell development in the fetal liver. Gli3 functions to repress Shh expression, and Shh signals to developing B cells to regulate their development at multiple developmental stages.
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Ubieta at al. describe the function of the Fra-2/AP-1 transcription factor as a regulator of Foxo1 and Irf4 expression in B cells. Fra-2 affects B cell proliferation and maintains their number in bone marrow.
Combining high-coverage whole-genome sequencing with functional analyses, Giessler et al. demonstrate that tumor initiation and long-term tumor formation in human colorectal cancer are driven by multiple genomic subclones and that the functional heterogeneity of colorectal cancer tumor clone–initiating cells is not based on genomic architecture.
CD177 presents antigens in allo- and autoimmune diseases on the neutrophil surface. Eulenberg-Gustavus et al. show that epigenetic silencing causes CD177negative neutrophils, whereas a novel pattern of monoallelic CD177 expression results in a variable percentage of CD177positive neutrophils in bimodal individuals.
Lood et al. find that neutrophil TLR7/8 activation shifts neutrophils from phagocytosis of immune complexes to NETosis. Reduced phagocytosis of immune complexes is associated with partial proteolytic cleavage of FcgRIIA. Cleaved FcgRIIA is found in SLE neutrophils ex vivo.
Uderhardt et al. show that eosinophils accumulate in freshly formed thrombi, where they provide a procoagulant surface that is rich in oxidized phospholipids and allows assembly and activation of plasmatic coagulation factors. This mechanism stabilizes the thrombus and enables hemostasis but also contributes to thrombotic disease.
Heit et al. describe that in humans, circulating memory T follicular helper cells (cTfh) have a clonal relationship to germinal center Tfh (GCTfh) cells. Upon vaccination, such memory cTfh respond with clonal expansion, activation, and simultaneous expression of a GCTfh-like phenotype.
Daniel et al. have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Bergman et al. now challenge these results.
In this issue of JEM, Bergman et al. challenge the data published in a previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Daniel et al. provide a response to these data.
Correction: Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT