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ARID5B regulates metabolic programming in human adaptive NK cells
Natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. Here, we explored the metabolic processes unique to these cells. Adaptive CD3–CD56dimCD57+NKG2C+ NK cells exhibited metabolic hallmarks of lymphocyte memory, including increased oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we found that a short isoform of the chromatin-modifying transcriptional regulator, AT-rich interaction domain 5B (ARID5B), was selectively induced through DNA hypomethylation in adaptive NK cells. Knockd...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Cichocki, F., Wu, C.-Y., Zhang, B., Felices, M., Tesi, B., Tuininga, K., Dougherty, P., Taras, E., Hinderlie, P., Blazar, B. R., Bryceson, Y. T., Miller, J. S. Tags: Innate Immunity and Inflammation, Metabolism Articles Source Type: research

TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading
The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Martini-Stoica, H., Cole, A. L., Swartzlander, D. B., Chen, F., Wan, Y.-W., Bajaj, L., Bader, D. A., Lee, V. M. Y., Trojanowski, J. Q., Liu, Z., Sardiello, M., Zheng, H. Tags: Neuroscience Articles Source Type: research

hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia
We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein–coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Mackie, D. I., Al Mutairi, F., Davis, R. B., Kechele, D. O., Nielsen, N. R., Snyder, J. C., Caron, M. G., Kliman, H. J., Berg, J. S., Simms, J., Poyner, D. R., Caron, K. M. Tags: Cardiovascular Biology, Human Disease Genetics Articles Source Type: research

Identification of non-mutated neoantigens presented by TAP-deficient tumors
Most T cell–based immunotherapies of cancer depend on intact antigen presentation by HLA class I molecules (HLA-I). However, defects in the antigen-processing machinery can cause downregulation of HLA-I, rendering tumor cells resistant to CD8+ T cells. Previously, we demonstrated that a unique category of cancer antigens is selectively presented by tumor cells deficient for the peptide transporter TAP, enabling a specific attack of such tumors without causing immunopathology in mouse models. With a novel combinatorial screening approach, we now identify 16 antigens of this category in humans. These HLA-A*02:01 presen...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Marijt, K. A., Blijleven, L., Verdegaal, E. M. E., Kester, M. G., Kowalewski, D. J., Rammensee, H.-G., Stevanovic, S., Heemskerk, M. H. M., van der Burg, S. H., van Hall, T. Tags: Tumor Immunology Articles Source Type: research

Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117
In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Cohen, Y. Z., Lorenzi, J. C. C., Krassnig, L., Barton, J. P., Burke, L., Pai, J., Lu, C.-L., Mendoza, P., Oliveira, T. Y., Sleckman, C., Millard, K., Butler, A. L., Dizon, J. P., Belblidia, S. A., Witmer-Pack, M., Shimeliovich, I., Gulick, R. M., Seaman, Tags: Infectious Disease and Host Defense Articles Source Type: research

The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to {beta}-papillomaviruses
We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and -HPV4, respe...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: de Jong, S. J., Crequer, A., Matos, I., Hum, D., Gunasekharan, V., Lorenzo, L., Jabot-Hanin, F., Imahorn, E., Arias, A. A., Vahidnezhad, H., Youssefian, L., Markle, J. G., Patin, E., DAmico, A., Wang, C. Q. F., Full, F., Ensser, A., Leisner, T. M., Parise Tags: Immunodeficiency, Infectious Disease and Host Defense, Human Disease Genetics Articles Source Type: research

Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation
Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11–processing dead KI mice (Casp11Prc D285A/D285A) ex...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Lee, B. L., Stowe, I. B., Gupta, A., Kornfeld, O. S., Roose-Girma, M., Anderson, K., Warming, S., Zhang, J., Lee, W. P., Kayagaki, N. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense Brief Definitive Reports Source Type: research

Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells
We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor an...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Lau, C. M., Tiniakou, I., Perez, O. A., Kirkling, M. E., Yap, G. S., Hock, H., Reizis, B. Tags: Innate Immunity and Inflammation, Tumor Immunology Brief Definitive Reports Source Type: research

TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimers disease
There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-me...
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Chakrabarty, P., Li, A., Ladd, T. B., Strickland, M. R., Koller, E. J., Burgess, J. D., Funk, C. C., Cruz, P. E., Allen, M., Yaroshenko, M., Wang, X., Younkin, C., Reddy, J., Lohrer, B., Mehrke, L., Moore, B. D., Liu, X., Ceballos-Diaz, C., Rosario, A. M. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Brief Definitive Reports Source Type: research

Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau
This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Kang, S. S., Ebbert, M. T. W., Baker, K. E., Cook, C., Wang, X., Sens, J. P., Kocher, J.-P., Petrucelli, L., Fryer, J. D. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Brief Definitive Reports Source Type: research

Refusing to TAP out: 16 new human TEIPPs identified
In this issue of JEM, Marijt et al. (https://doi.org/10.1084/jem.20180577) report their discovery of 16 novel human TAP-independent TEIPP peptides, whereas only one had been previously identified. This opens the door to new therapeutic options for patients with TAP-deficient tumors. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Gigoux, M., Wolchok, J. Tags: Insights Source Type: research

HPV: CIB1 is for EVER and EVER
In this issue, de Jong et al. (https://doi.org/10.1084/jem.20170308) identify bi-allelic loss-of-expression, loss-of-function mutations of the calcium- and integrin-binding protein 1 (CIB1) gene as a new cause of epidermodysplasia verruciformis (EV) and demonstrate that the CIB1 interacts with the EVER1 and EVER2 proteins to form a complex involved in keratinocyte-intrinsic immune response to human β-papillomaviruses (β-HPVs). (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - September 3, 2018 Category: Internal Medicine Authors: Notarangelo, L. D. Tags: Insights Source Type: research

Correction: SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-{beta} signaling
Vol. 215, No. 5, May 7, 2018. 10.1084/jem.20171477. The authors regret that Edward T.H. Yeh was inadvertently left off the original author list. The corrected author list appears above. The online article has been corrected accordingly. The... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Jiang, L., Han, X., Wang, J., Wang, C., Sun, X., Xie, J., Wu, G., Phan, H., Liu, Z., Yeh, E. T. H., Zhang, C., Zhao, M., Kang, X. Tags: Corrections Source Type: research

Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity
Tle/Groucho proteins are transcriptional corepressors interacting with Tcf/Lef and Runx transcription factors, but their physiological roles in T cell development remain unknown. Conditional targeting of Tle1, Tle3 and Tle4 revealed gene dose–dependent requirements for Tle proteins in CD8+ lineage cells. Upon ablating all three Tle proteins, generation of CD8+ T cells was greatly diminished, largely owing to redirection of MHC-I–selected thymocytes to CD4+ lineage; the remaining CD8-positive T cells showed aberrant up-regulation of CD4+ lineage-associated genes including Cd4, Thpok, ...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Xing, S., Shao, P., Li, F., Zhao, X., Seo, W., Wheat, J. C., Ramasamy, S., Wang, J., Li, X., Peng, W., Yu, S., Liu, C., Taniuchi, I., Sweetser, D. A., Xue, H.-H. Tags: Articles Source Type: research

NQO1 inhibits the TLR-dependent production of selective cytokines by promoting I{kappa}B-{zeta} degradation
In this study, we found a novel role of NQO1 in suppressing Toll-like receptor (TLR)–mediated innate immune responses. NQO1-deficient macrophages selectively produced excessive amounts of IL-6, IL-12, and GM-CSF on LPS stimulation, and the deletion of NQO1 in macrophages exacerbated LPS-induced septic shock. NQO1 interacted with the nuclear IB protein IB-, which is essential for the TLR-mediated induction of a subset of secondary response genes, including IL-6, and promoted IB- degradation in a ubiquitin-dependent manner. We demonstrated that PDLIM2, known as the ubiquitin E3 ligase, participates in NQO1-dependent IB...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Kimura, A., Kitajima, M., Nishida, K., Serada, S., Fujimoto, M., Naka, T., Fujii-Kuriyama, Y., Sakamato, S., Ito, T., Handa, H., Tanaka, T., Yoshimura, A., Suzuki, H. Tags: Innate Immunity and Inflammation Articles Source Type: research