Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils
Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Ohayon, D., De Chiara, A., Dang, P. M.-C., Thieblemont, N., Chatfield, S., Marzaioli, V., Burgener, S. S., Mocek, J., Candalh, C., Pintard, C., Tacnet-Delorme, P., Renault, G., Lagoutte, I., Favier, M., Walker, F., Hurtado-Nedelec, M., Desplancq, D., Weis Tags: Innate Immunity and Inflammation Articles Source Type: research

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription
Innate lymphoid cells (ILCs) play critical roles in defending infections and maintaining mucosal homeostasis. All ILCs arise from common lymphoid progenitors (CLPs) in bone marrow. However, how CLPs stratify and differentiate into ILC lineages remains elusive. Here, we showed that Yeats4 is highly expressed in ILCs and their progenitors. Yeats4 conditional KO in the hematopoietic system causes decreased numbers of ILCs and impairs their effector functions. Moreover, Yeats4 regulates α4β7+ CLP differentiation toward common helper ILC progenitors (CHILPs). Mechanistically, Yeats4 recruits the Dot1l–RNA Pol I...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Liu, B., Yang, L., Zhu, X., Li, H., Zhu, P., Wu, J., Lu, T., He, L., Liu, N., Meng, S., Zhou, L., Ye, B., Tian, Y., Fan, Z. Tags: Articles Source Type: research

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion
Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Zarei, M., Du, H., Nassar, A. H., Yan, R. E., Giannikou, K., Johnson, S. H., Lam, H. C., Henske, E. P., Wang, Y., Zhang, T., Asara, J., Kwiatkowski, D. J. Tags: Solid Tumors Articles Source Type: research

Host conditioning with IL-1{beta} improves the antitumor function of adoptively transferred T cells
Host conditioning has emerged as an important component of effective adoptive cell transfer–based immunotherapy for cancer. High levels of IL-1β are induced by host conditioning, but its impact on the antitumor function of T cells remains unclear. We found that the administration of IL-1β increased the population size and functionality of adoptively transferred T cells within the tumor. Most importantly, IL-1β enhanced the ability of tumor-specific T cells to trigger the regression of large, established B16 melanoma tumors in mice. Mechanistically, we showed that the increase in T cell numbers was asso...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Lee, P.-H., Yamamoto, T. N., Gurusamy, D., Sukumar, M., Yu, Z., Hu-Li, J., Kawabe, T., Gangaplara, A., Kishton, R. J., Henning, A. N., Vodnala, S. K., Germain, R. N., Paul, W. E., Restifo, N. P. Tags: Innate Immunity and Inflammation, Tumor Immunology Articles Source Type: research

The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function
We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled Nlrp6–/–, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in Il18–/– mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus Adlercrutzia co...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Volk, J. K., Nyström, E. E. L., van der Post, S., Abad, B. M., Schroeder, B. O., Johansson, A., Svensson, F., Jäverfelt, S., Johansson, M. E. V., Hansson, G. C., Birchenough, G. M. H. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

Endothelial IQGAP1 regulates leukocyte transmigration by directing the LBRC to the site of diapedesis
Transendothelial migration (TEM) of leukocytes across the endothelium is critical for inflammation. In the endothelium, TEM requires the coordination of membrane movements and cytoskeletal interactions, including, prominently, recruitment of the lateral border recycling compartment (LBRC). The scaffold protein IQGAP1 was recently identified in a screen for LBRC-interacting proteins. Knockdown of endothelial IQGAP1 disrupted the directed movement of the LBRC and substantially reduced leukocyte TEM. Expression of truncated IQGAP1 constructs demonstrated that the calponin homology domain is required for IQGAP1 localization to...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Sullivan, D. P., Dalal, P. J., Jaulin, F., Sacks, D. B., Kreitzer, G., Muller, W. A. Tags: Cardiovascular Biology, Innate Immunity and Inflammation Articles Source Type: research

Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activati...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Li, S., Wu, Y., Yang, D., Wu, C., Ma, C., Liu, X., Moynagh, P. N., Wang, B., Hu, G., Yang, S. Tags: Neuroinflammation, Innate Immunity and Inflammation Articles Source Type: research

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Chronic activation of brain innate immunity is a prominent feature of Alzheimer’s disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., Holtzman, D. M. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

TGF{beta} signaling in germinal center B cells promotes the transition from light zone to dark zone
B cells in germinal centers (GCs) cycle between light zone (LZ) and dark zone (DZ). The cues in the GC microenvironment that regulate the transition from LZ to DZ have not been well characterized. In Peyer’s patches (PPs), transforming growth factor-β (TGFβ) promotes IgA induction in activated B cells that can then differentiate into GC B cells. We show here that TGFβ signaling occurs in B cells in GCs and is distinct from signaling that occurs in activated B cells in PPs. Whereas in activated B cells TGFβ signaling is required for IgA induction, in the GC it was instead required for the transitio...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Albright, A. R., Kabat, J., Li, M., Raso, F., Reboldi, A., Muppidi, J. R. Tags: Mucosal Immunology Articles Source Type: research

Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity
The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)–relay neu...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Bradley, P. M., Denecke, C. K., Aljovic, A., Schmalz, A., Kerschensteiner, M., Bareyre, F. M. Tags: Neuroscience Brief Definitive Reports Source Type: research

Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels
The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end o...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Ma, Q., Decker, Y., Müller, A., Ineichen, B. V., Proulx, S. T. Tags: Cardiovascular Biology, Neuroscience Brief Definitive Reports Source Type: research

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes
Hypothalamic–pituitary–adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Futch, H. S., McFarland, K. N., Moore, B. D., Kuhn, M. Z., Giasson, B. I., Ladd, T. B., Scott, K. A., Shapiro, M. R., Nosacka, R. L., Goodwin, M. S., Ran, Y., Cruz, P. E., Ryu, D. H., Croft, C. L., Levites, Y., Janus, C., Chakrabarty, P., Judge, A. R., Br Tags: Neuroscience, Metabolism Brief Definitive Reports Source Type: research

IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus
Regulatory T (T reg) cells, a specialized subset of CD4+ T cells, are essential to prevent fatal autoimmunity. Expression of the T reg lineage-defining transcription factor Foxp3, and therefore their differentiation in the thymus, is dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that the majority of IL-2–producing cells in the thymus are mature CD4 single-positive (CD4SP) thymocytes and that continuous IL-2 production sustained thymic T reg cell generation and control of systemic immune activation. Furthermore, single-cell RNA sequencing analysis of CD4 thymocyte subsets rev...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Hemmers, S., Schizas, M., Azizi, E., Dikiy, S., Zhong, Y., Feng, Y., Altan-Bonnet, G., Rudensky, A. Y. Tags: Autoimmunity, Tolerance Brief Definitive Reports Source Type: research

Gasdermins and their role in immunity and inflammation
The gasdermins are a family of pore-forming proteins recently implicated in the immune response. One of these proteins, gasdermin D (GSDMD), has been identified as the executioner of pyroptosis, an inflammatory form of lytic cell death that is induced upon formation of caspase-1–activating inflammasomes. The related proteins GSDME and GSDMA have also been implicated in autoimmune diseases and certain cancers. Most gasdermin proteins are believed to have pore-forming capabilities. The best-studied member, GSDMD, controls the release of the proinflammatory cytokines IL-1ß and IL-18 and pyroptotic cell death. Beca...
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Orning, P., Lien, E., Fitzgerald, K. A. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Review Source Type: research

Arkaitz Carracedo: If the scientific question is good, the result will be interesting
Arkaitz Carracedo is a principal investigator at the Association for Cooperative Research in Biosciences (CIC bioGUNE) in Spain; his laboratory focuses on signaling and metabolic alterations in cancer. Arkaitz has investigated the regulation of fatty acid oxidation in cancer cells and how these changes could be manipulated therapeutically. We chatted with Arkaitz to find out about his career in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

Death by microglia
The roles of microglia and ApoE in tauopathies, such as Alzheimer’s disease, remain elusive. In this issue, Shi et al. (https://doi.org/10.1084/jem.20190980) demonstrate that microglia-mediated innate immunity collaborates with ApoE to drive neurodegeneration and disease progression in a mouse model of tauopathy. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 4, 2019 Category: Internal Medicine Authors: Kemal, S., Vassar, R. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Insights Source Type: research

Correction: Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer
Vol. 216, No. 3, March 4, 2019. 10.1084/jem.20180765. The authors regret that in their original paper, the Masson’s image of the control group in Fig. 7 J was incorrect as a result of an error... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Gao, Q., Yang, Z., Xu, S., Li, X., Yang, X., Jin, P., Liu, Y., Zhou, X., Zhang, T., Gong, C., Wei, X., Liu, D., Sun, C., Chen, G., Hu, J., Meng, L., Zhou, J., Sawada, K., Fruscio, R., Grunt, T. W., Wischhusen, J., Vargas-Hernandez, V. M., Pothuri, B., Col Tags: Corrections Source Type: research

RRAS2 shapes the TCR repertoire by setting the threshold for negative selection
Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2–/– mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimm...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Martinez-Riano, A., Bovolenta, E. R., Boccasavia, V. L., Ponomarenko, J., Abia, D., Oeste, C. L., Fresno, M., van Santen, H. M., Alarcon, B. Tags: Autoimmunity, Tolerance Articles Source Type: research

Resident memory CD8 T cells persist for years in human small intestine
Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for>1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intes...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Bartolome-Casado, R., Landsverk, O. J. B., Chauhan, S. K., Richter, L., Phung, D., Greiff, V., Risnes, L. F., Yao, Y., Neumann, R. S., Yaqub, S., Oyen, O., Horneland, R., Aandahl, E. M., Paulsen, V., Sollid, L. M., Qiao, S.-W., Baekkevold, E. S., Jahnsen, Tags: Mucosal Immunology Articles Source Type: research

Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression
Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti–PD-1 checkpoint therapy. Specific depletion of the CD163+ macrophages results in a massive infiltration of ...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Etzerodt, A., Tsalkitzi, K., Maniecki, M., Damsky, W., Delfini, M., Baudoin, E., Moulin, M., Bosenberg, M., Graversen, J. H., Auphan-Anezin, N., Moestrup, S. K., Lawrence, T. Tags: Solid Tumors, Innate Immunity and Inflammation, Tumor Immunology Articles Source Type: research

Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer
Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and ...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Zhu, W., Miyata, N., Winter, M. G., Arenales, A., Hughes, E. R., Spiga, L., Kim, J., Sifuentes-Dominguez, L., Starokadomskyy, P., Gopal, P., Byndloss, M. X., Santos, R. L., Burstein, E., Winter, S. E. Tags: Mucosal Immunology Articles Source Type: research

CD97 is a critical regulator of acute myeloid leukemia stem cell function
Despite significant efforts to improve therapies for acute myeloid leukemia (AML), clinical outcomes remain poor. Understanding the mechanisms that regulate the development and maintenance of leukemic stem cells (LSCs) is important to reveal new therapeutic opportunities. We have identified CD97, a member of the adhesion class of G protein–coupled receptors (GPCRs), as a frequently up-regulated antigen on AML blasts that is a critical regulator of blast function. High levels of CD97 correlate with poor prognosis, and silencing of CD97 reduces disease aggressiveness in vivo. These phenotypes are due to CD97’s ab...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Martin, G. H., Roy, N., Chakraborty, S., Desrichard, A., Chung, S. S., Woolthuis, C. M., Hu, W., Berezniuk, I., Garrett-Bakelman, F. E., Hamann, J., Devlin, S. M., Chan, T. A., Park, C. Y. Tags: Leukemia & Lymphoma, Stem Cells & Regeneration, Hematopoiesis Articles Source Type: research

Impact of naturally forming human {alpha}/{beta}-tryptase heterotetramers in the pathogenesis of hereditary {alpha}-tryptasemia
Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Le, Q. T., Lyons, J. J., Naranjo, A. N., Olivera, A., Lazarus, R. A., Metcalfe, D. D., Milner, J. D., Schwartz, L. B. Tags: Innate Immunity and Inflammation Articles Source Type: research

Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes
Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells ex...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Bancroft, T., DeBuysscher, B. L., Weidle, C., Schwartz, A., Wall, A., Gray, M. D., Feng, J., Steach, H. R., Fitzpatrick, K. S., Gewe, M. M., Skog, P. D., Doyle-Cooper, C., Ota, T., Strong, R. K., Nemazee, D., Pancera, M., Stamatatos, L., McGuire, A. T., T Tags: Infectious Disease and Host Defense Articles Source Type: research

Anti-idiotypic antibodies elicit anti-HIV-1-specific B cell responses
Human anti-HIV-1 broadly neutralizing antibodies (bNAbs) protect against infection in animal models. However, bNAbs have not been elicited by vaccination in diverse wild-type animals or humans, in part because B cells expressing the precursors of these antibodies do not recognize most HIV-1 envelopes (Envs). Immunogens have been designed that activate these B cell precursors in vivo, but they also activate competing off-target responses. Here we report on a complementary approach to expand specific B cells using an anti-idiotypic antibody, iv8, that selects for naive human B cells expressing immunoglobulin light chains wit...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Dosenovic, P., Pettersson, A.-K., Wall, A., Thientosapol, E. S., Feng, J., Weidle, C., Bhullar, K., Kara, E. E., Hartweger, H., Pai, J. A., Gray, M. D., Parks, K. R., Taylor, J. J., Pancera, M., Stamatatos, L., Nussenzweig, M. C., McGuire, A. T. Tags: Infectious Disease and Host Defense Articles Source Type: research

Risk of Zika microcephaly correlates with features of maternal antibodies
We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Robbiani, D. F., Olsen, P. C., Costa, F., Wang, Q., Oliveira, T. Y., Nery, N., Aromolaran, A., do Rosario, M. S., Sacramento, G. A., Cruz, J. S., Khouri, R., Wunder, E. A., Mattos, A., de Paula Freitas, B., Sarno, M., Archanjo, G., Daltro, D., Carvalho, G Tags: Infectious Disease and Host Defense Articles Source Type: research

Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity
Despite causing outbreaks of fever and arthritis in multiple countries, no countermeasures exist against Mayaro virus (MAYV), an emerging mosquito-transmitted alphavirus. We generated 18 neutralizing mAbs against MAYV, 11 of which had "elite" activity that inhibited infection with EC50 values of
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Earnest, J. T., Basore, K., Roy, V., Bailey, A. L., Wang, D., Alter, G., Fremont, D. H., Diamond, M. S. Tags: Infectious Disease and Host Defense Articles Source Type: research

CSF-1 controls cerebellar microglia and is required for motor function and social interaction
Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cereb...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Kana, V., Desland, F. A., Casanova-Acebes, M., Ayata, P., Badimon, A., Nabel, E., Yamamuro, K., Sneeboer, M., Tan, I.-L., Flanigan, M. E., Rose, S. A., Chang, C., Leader, A., Le Bourhis, H., Sweet, E. S., Tung, N., Wroblewska, A., Lavin, Y., See, P., Bacc Tags: Neuroinflammation Articles Source Type: research

Embryonic FAP+ lymphoid tissue organizer cells generate the reticular network of adult lymph nodes
The induction of adaptive immunity is dependent on the structural organization of LNs, which is in turn governed by the stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace the developmental origin of mesenchymal LN stromal cells (mLNSCs) to a previously undescribed embryonic fibroblast activation protein-α (FAP)+ progenitor. FAP+ cells of the LN anlagen express lymphotoxin β receptor (LTβR) and vascular cell adhesion molecule (VCAM), but not intercellular adhesion molecule (ICAM), suggesting they are early mesenchymal lymphoid tissue organizer (mLTo) cells. Clonal l...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Denton, A. E., Carr, E. J., Magiera, L. P., Watts, A. J. B., Fearon, D. T. Tags: Infectious Disease and Host Defense Brief Definitive Reports Source Type: research

ILC3s integrate glycolysis and mitochondrial production of reactive oxygen species to fulfill activation demands
Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and produ...
Source: The Journal of Experimental Medicine - October 7, 2019 Category: Internal Medicine Authors: Di Luccia, B., Gilfillan, S., Cella, M., Colonna, M., Huang, S. C.-C. Tags: Innate Immunity and Inflammation, Mucosal Immunology, Metabolism Brief Definitive Reports Source Type: research

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 7, 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 7, 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 7, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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 2, 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

The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF
This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 2, 2019 Category: Internal Medicine Authors: Vetters, J., van Helden, M. J., Wahlen, S., Tavernier, S. J., Martens, A., Fayazpour, F., Vergote, K., Vanheerswynghels, M., Deswarte, K., Van Moorleghem, J., De Prijck, S., Takahashi, N., Vandenabeele, P., Boon, L., van Loo, G., Vivier, E., Lambrecht, B. Tags: Innate Immunity and Inflammation Brief Definitive Reports Source Type: research

A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue
Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between the stroma and adipose-resident immune cells is less well understood. We identify that white adipose tissue–resident multipotent stromal cells (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals for sustaining ILC2. Indeed, we demonstrate that WAT-MSCs also support ICAM-1–mediated proliferation and activation of LFA-1–expressing ILC2s. Consequently, ILC2-derived IL-4 and IL-13 fee...
Source: The Journal of Experimental Medicine - September 2, 2019 Category: Internal Medicine Authors: Rana, B. M. J., Jou, E., Barlow, J. L., Rodriguez-Rodriguez, N., Walker, J. A., Knox, C., Jolin, H. E., Hardman, C. S., Sivasubramaniam, M., Szeto, A., Cohen, E. S., Scott, I. C., Sleeman, M. A., Chidomere, C. I., Cruz Migoni, S., Caamano, J., Jorgensen, Tags: Brief Definitive Reports Source Type: research

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses
This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 2, 2019 Category: Internal Medicine Authors: Spencer, S., Köstel Bal, S., Egner, W., Lango Allen, H., Raza, S. I., Ma, C. A., Gürel, M., Zhang, Y., Sun, G., Sabroe, R. A., Greene, D., Rae, W., Shahin, T., Kania, K., Ardy, R. C., Thian, M., Staples, E., Pecchia-Bekkum, A., Worrall, W. Tags: Immunodeficiency Brief Definitive Reports Source Type: research

A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection
Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here. (Source: The J...
Source: The Journal of Experimental Medicine - September 2, 2019 Category: Internal Medicine Authors: Barrat, F. J., Su, L. Tags: Autoimmunity, Innate Immunity and Inflammation, Infectious Disease and Host Defense Review Source Type: research

Ross Levine: Focus on the critical questions
Ross Levine is a physician-scientist at Memorial Sloan Kettering Cancer Center in New York, where his laboratory studies the genetic basis of myeloid malignancies. Work from Ross’ laboratory has shown how mutations in the JAK–STAT pathway and epigenetic regulators play a role in myeloproliferative neoplasms, and JAK inhibitors are now successfully used to treat myeloproliferative neoplasms. We spoke to Ross about his journey in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 2, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research