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When alpha meets beta, mast cells get hyper
The evolutionary conservation of the catalytically inactive α-tryptase gene has remained a mystery. In this issue of JEM, Le et al. (2019. J. Exp. Med. https://doi.org/10.1084/jem.20190701) unveil the existence of a novel but natural tryptase, heteromeric α/β-tryptase, a critical mediator of α-tryptase–associated diseases. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 6, 2019 Category: Internal Medicine Authors: Ong, M. S., Tergaonkar, V. Tags: Infectious Disease and Host Defense, Human Disease Genetics Insights Source Type: research

Antibody barriers to going viral
Antibody neutralization of a virus in vitro is often associated with protection against viral exposure in vivo, but the mechanisms operational in vivo are often unclear. By investigating a large number of antibodies, Earnest et al. (https://doi.org/10.1084/jem.20190736) show the importance of antibody effector function in neutralizing antibody protection against an emerging alphavirus in a mouse model. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 6, 2019 Category: Internal Medicine Authors: Burton, D. R. Tags: Insights Source Type: research

Microglia: Same same, but different
Microglial identity in the central nervous system (CNS) is dependent on colony stimulating factor 1 receptor (CSF-1R) signaling and its ligands IL-34 and colony stimulating factor 1 (CSF-1). In this issue of JEM, Kana et al. (https://doi.org/10.1084/jem.20182037) make the important discovery that CSF-1, but not IL-34, orchestrates cerebellar microglial homeostasis in mice, and its deficiency resulted in severe cerebellar dysfunctions accompanied by defects in motor function and social behavior. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 6, 2019 Category: Internal Medicine Authors: Kierdorf, K., Prinz, M. Tags: Neuroinflammation Insights Source Type: research

Correction: KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2- ILCs biased toward ILC2 or ILC3
Vol. 216, No. 8, August 5, 2019. 10.1084/jem.20190490. JEM regrets that in the original version of this paper, panels E-G were mistakenly omitted from Fig. 4 due to a production error. The corrected and complete (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Nagasawa, M., Heesters, B. A., Kradolfer, C. M. A., Krabbendam, L., Martinez-Gonzalez, I., de Bruijn, M. J. W., Golebski, K., Hendriks, R. W., Stadhouders, R., Spits, H., Bal, S. M. Tags: Corrections Source Type: research

Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli
We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)–phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces O-GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 O-GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithe...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Lee, H., Li, C., Zhang, Y., Zhang, D., Otterbein, L. E., Jin, Y. Tags: Innate Immunity and Inflammation, Mucosal Immunology Articles Source Type: research

Sensing of apoptotic cells through Axl causes lung basal cell proliferation in inflammatory diseases
Epithelial cell proliferation, division, and differentiation are critical for barrier repair following inflammation, but the initial trigger for this process is unknown. Here we define that sensing of apoptotic cells by the TAM receptor tyrosine kinase Axl is a critical indicator for tracheal basal cell expansion, cell cycle reentry, and symmetrical cell division. Furthermore, once the pool of tracheal basal cells has expanded, silencing of Axl is required for their differentiation. Genetic depletion of Axl triggers asymmetrical cell division, leading to epithelial differentiation and ciliated cell regeneration. This disco...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Fujino, N., Brand, O. J., Morgan, D. J., Fujimori, T., Grabiec, A. M., Jagger, C. P., Maciewicz, R. A., Yamada, M., Itakura, K., Sugiura, H., Ichinose, M., Hussell, T. Tags: Stem Cells & Regeneration, Innate Immunity and Inflammation, Mucosal Immunology Articles Source Type: research

The E3 ubiquitin ligase Itch restricts antigen-driven B cell responses
The E3 ubiquitin ligase Itch regulates antibody levels and prevents autoimmune disease in humans and mice, yet how Itch regulates B cell fate or function is unknown. We now show that Itch directly limits B cell activity. While Itch-deficient mice displayed normal numbers of preimmune B cell populations, they showed elevated numbers of antigen-experienced B cells. Mixed bone marrow chimeras revealed that Itch acts within B cells to limit naive and, to a greater extent, germinal center (GC) B cell numbers. B cells lacking Itch exhibited increased proliferation, glycolytic capacity, and mTORC1 activation. Moreover, stimulatio...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Moser, E. K., Roof, J., Dybas, J. M., Spruce, L. A., Seeholzer, S. H., Cancro, M. P., Oliver, P. M. Tags: Autoimmunity, Metabolism Articles Source Type: research

Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs
We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mic...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Mastio, J., Condamine, T., Dominguez, G., Kossenkov, A. V., Donthireddy, L., Veglia, F., Lin, C., Wang, F., Fu, S., Zhou, J., Viatour, P., Lavilla-Alonso, S., Polo, A. T., Tcyganov, E. N., Mulligan, C., Nam, B., Bennett, J., Masters, G., Guarino, M., Kuma Tags: Tumor Immunology Articles Source Type: research

Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer
High numbers of tissue-resident memory T (TRM) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1–expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1–expressing non-TRM cells. This feature was more prominent in the T...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Clarke, J., Panwar, B., Madrigal, A., Singh, D., Gujar, R., Wood, O., Chee, S. J., Eschweiler, S., King, E. V., Awad, A. S., Hanley, C. J., McCann, K. J., Bhattacharyya, S., Woo, E., Alzetani, A., Seumois, G., Thomas, G. J., Ganesan, A.-P., Friedmann, P. Tags: Solid Tumors, Tumor Immunology Articles Source Type: research

NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing
NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor–mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perfor...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Prager, I., Liesche, C., van Ooijen, H., Urlaub, D., Verron, Q., Sandström, N., Fasbender, F., Claus, M., Eils, R., Beaudouin, J., Önfelt, B., Watzl, C. Tags: Innate Immunity and Inflammation, Tumor Immunology Articles Source Type: research

Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells
We report that palmitoyl-protein thioesterase 1 (PPT1), which catabolizes lipid-modified proteins in neurons, is highly expressed in cDC1s. PPT1-deficient DCs are more susceptible to vesicular stomatitis virus (VSV) infection, and mice with PPT1 deficiency in cDC1s show impaired response to VSV. Conversely, PPT1-deficient cDC1s enhance the priming of naive CD8+ T cells into tissue-resident KLRG1+ effectors and memory T cells, resulting in rapid clearance of tumors and Listeria monocytogenes. Mechanistically, PPT1 protects steady state DCs from viruses by promoting antigen degradation and endosomal acidification via V-ATPas...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Ou, P., Wen, L., Liu, X., Huang, J., Huang, X., Su, C., Wang, L., Ni, H., Reizis, B., Yang, C. Y. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells
Perturbations in B cells are a hallmark of HIV-1 infection. This is signified by increased numbers of exhausted CD21neg memory B cells, driven by continuous antigen-specific and bystander activation. Using high-dimensional flow cytometry, we demonstrate that this exhausted phenotype is also prevalent among peripheral antigen-inexperienced naive and marginal zone (MZ) B cells in acute and chronic HIV-1 infection. A substantial fraction of naive and MZ B cells exhibit down-regulated CD21 levels and diminished response to B cell receptor (BCR)–dependent stimulation. Compared with CD21pos subsets, the CD21neg naive and M...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Liechti, T., Kadelka, C., Braun, D. L., Kuster, H., Böni, J., Robbiani, M., Günthard, H. F., Trkola, A. Tags: Infectious Disease and Host Defense Articles Source Type: research

Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines
We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threateni...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Hernandez, N., Bucciol, G., Moens, L., Le Pen, J., Shahrooei, M., Goudouris, E., Shirkani, A., Changi-Ashtiani, M., Rokni-Zadeh, H., Sayar, E. H., Reisli, I., Lefevre-Utile, A., Zijlmans, D., Jurado, A., Pholien, R., Drutman, S., Belkaya, S., Cobat, A., B Tags: Immunodeficiency, Innate Immunity and Inflammation, Infectious Disease and Host Defense Articles Source Type: research

Severe influenza pneumonitis in children with inherited TLR3 deficiency
We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -, and display enhanced viral susceptibility, upon IAV infe...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Lim, H. K., Huang, S. X. L., Chen, J., Kerner, G., Gilliaux, O., Bastard, P., Dobbs, K., Hernandez, N., Goudin, N., Hasek, M. L., Garcia Reino, E. J., Lafaille, F. G., Lorenzo, L., Luthra, P., Kochetkov, T., Bigio, B., Boucherit, S., Rozenberg, F., Vedrin Tags: Immunodeficiency, Infectious Disease and Host Defense, Human Disease Genetics Articles Source Type: research

The epigenetic regulator ATF7ip inhibits Il2 expression, regulating Th17 responses
T helper 17 cells (Th17) are critical for fighting infections at mucosal surfaces; however, they have also been found to contribute to the pathogenesis of multiple autoimmune diseases and have been targeted therapeutically. Due to the role of Th17 cells in autoimmune pathogenesis, it is important to understand the factors that control Th17 development. Here we identify the activating transcription factor 7 interacting protein (ATF7ip) as a critical regulator of Th17 differentiation. Mice with T cell–specific deletion of Atf7ip have impaired Th17 differentiation secondary to the aberrant overproduction of IL-2 with T ...
Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Sin, J. H., Zuckerman, C., Cortez, J. T., Eckalbar, W. L., Erle, D. J., Anderson, M. S., Waterfield, M. R. Tags: Autoimmunity, Tolerance Brief Definitive Reports Source Type: research