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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 3, 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 6, 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 6, 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 inte...
Source: The Journal of Experimental Medicine - October 6, 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 6, 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 6, 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 6, 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 6, 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 6, 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 6, 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 < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly. (Source: The ...
Source: The Journal of Experimental Medicine - October 6, 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 <10 ng/ml. Antibodies with the greatest inhibitory capacity in cell culture mapped to epitopes near the fusion peptide of E1 and in domain B of the E2 glycoproteins. Unexpectedly, many of the elite neutralizing mAbs failed to prevent MAYV infection and disease in vivo. Instead, the most protective mAbs bound viral antigen on the...
Source: The Journal of Experimental Medicine - October 6, 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 6, 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 6, 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 6, 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