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The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors
Lymphocyte migration is mediated by G protein–coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through β-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Nakai, A., Fujimoto, J., Miyata, H., Stumm, R., Narazaki, M., Schulz, S., Baba, Y., Kumanogoh, A., Suzuki, K. Tags: Articles Source Type: research

Streptococcus pyogenes evades adaptive immunity through specific IgG glycan hydrolysis
Streptococcus pyogenes (Group A streptococcus; GAS) is a human pathogen causing diseases from uncomplicated tonsillitis to life-threatening invasive infections. GAS secretes EndoS, an endoglycosidase that specifically cleaves the conserved N-glycan on IgG antibodies. In vitro, removal of this glycan impairs IgG effector functions, but its relevance to GAS infection in vivo is unclear. Using targeted mass spectrometry, we characterized the effects of EndoS on host IgG glycosylation during the course of infections in humans. Substantial IgG glycan hydrolysis occurred at the site of infection and systemically in the severe ca...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Naegeli, A., Bratanis, E., Karlsson, C., Shannon, O., Kalluru, R., Linder, A., Malmström, J., Collin, M. Tags: Infectious Disease and Host Defense Articles Source Type: research

Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors
Before the emergence of hematopoietic stem cells (HSCs), lineage-restricted progenitors, such as erythro-myeloid progenitors (EMPs), are detected in the embryo or in pluripotent stem cell cultures in vitro. Although both HSCs and EMPs are derived from hemogenic endothelium, it remains unclear how and when these two developmental programs are segregated during ontogeny. Here, we show that hepatic leukemia factor (Hlf) expression specifically marks a developmental continuum between HSC precursors and HSCs. Using the Hlf-tdTomato reporter mouse, we found that Hlf is expressed in intra-aortic hematopoietic clusters and fetal l...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Yokomizo, T., Watanabe, N., Umemoto, T., Matsuo, J., Harai, R., Kihara, Y., Nakamura, E., Tada, N., Sato, T., Takaku, T., Shimono, A., Takizawa, H., Nakagata, N., Mori, S., Kurokawa, M., Tenen, D. G., Osato, M., Suda, T., Komatsu, N. Tags: Stem Cells & Regeneration, Hematopoiesis Articles Source Type: research

Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes
Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) activate G protein–coupled receptors (GPCRs) to regulate biological processes. Using a genome-wide CRISPR/dCas9–based GPCR signaling screen, LPAR1 was identified as an inducer of S1PR1/β-arrestin coupling while suppressing Gαi signaling. S1pr1 and Lpar1-positive lymphatic endothelial cells (LECs) of lymph nodes exhibit constitutive S1PR1/β-arrestin signaling, which was suppressed by LPAR1 antagonism. Pharmacological inhibition or genetic loss of function of Lpar1 reduced the frequency of punctate junctions at sinus-lining LECs. Ligand...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Hisano, Y., Kono, M., Cartier, A., Engelbrecht, E., Kano, K., Kawakami, K., Xiong, Y., Piao, W., Galvani, S., Yanagida, K., Kuo, A., Ono, Y., Ishida, S., Aoki, J., Proia, R. L., Bromberg, J. S., Inoue, A., Hla, T. Tags: Cardiovascular Biology Articles Source Type: research

Human lymphoid organ cDC2 and macrophages play complementary roles in T follicular helper responses
CD4+ T follicular helper (Tfh) cells are essential for inducing efficient humoral responses. T helper polarization is classically orientated by dendritic cells (DCs), which are composed of several subpopulations with distinct functions. Whether human DC subsets display functional specialization for Tfh polarization remains unclear. Here we find that tonsil cDC2 and CD14+ macrophages are the best inducers of Tfh polarization. This ability is intrinsic to the cDC2 lineage but tissue dependent for macrophages. We further show that human Tfh cells comprise two effector states producing either IL-21 or CXCL13. Distinct mechanis...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Durand, M., Walter, T., Pirnay, T., Naessens, T., Gueguen, P., Goudot, C., Lameiras, S., Chang, Q., Talaei, N., Ornatsky, O., Vassilevskaia, T., Baulande, S., Amigorena, S., Segura, E. Tags: Innate Immunity and Inflammation Articles Source Type: research

Sex-specific effects of microbiome perturbations on cerebral A{beta} amyloidosis and microglia phenotypes
We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE/presenilin 1 (PS1)E9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aβ amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aβ pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Dodiya, H. B., Kuntz, T., Shaik, S. M., Baufeld, C., Leibowitz, J., Zhang, X., Gottel, N., Zhang, X., Butovsky, O., Gilbert, J. A., Sisodia, S. S. Tags: Neuroscience Articles Source Type: research

Tumor suppression of novel anti-PD-1 antibodies mediated through CD28 costimulatory pathway
Classical antagonistic antibodies (Abs) targeting PD-1, such as pembrolizumab and nivolumab, act through blockade of the PD-1–PDL-1 interaction. Here, we have identified novel antagonistic anti–PD-1 Abs not blocking the PD-1–PDL-1 interaction. The nonblocking Abs recognize epitopes on PD-1 located on the opposing face of the PDL-1 interaction and overlap with a newly identified evolutionarily conserved patch. These nonblocking Abs act predominantly through the CD28 coreceptor. Importantly, a combination of blocking and nonblocking Abs synergize in the functional recovery of antigen-specific exhausted CD8 ...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Fenwick, C., Loredo-Varela, J.-L., Joo, V., Pellaton, C., Farina, A., Rajah, N., Esteves-Leuenberger, L., Decaillon, T., Suffiotti, M., Noto, A., Ohmiti, K., Gottardo, R., Weissenhorn, W., Pantaleo, G. Tags: Tumor Immunology Articles Source Type: research

c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma
The oncogenic c-MYC (MYC) transcription factor has broad effects on gene expression and cell behavior. We show that MYC alters the efficiency and quality of mRNA translation into functional proteins. Specifically, MYC drives the translation of most protein components of the electron transport chain in lymphoma cells, and many of these effects are independent from proliferation. Specific interactions of MYC-sensitive RNA-binding proteins (e.g., SRSF1/RBM42) with 5'UTR sequence motifs mediate many of these changes. Moreover, we observe a striking shift in translation initiation site usage. For example, in low-MYC conditions,...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Singh, K., Lin, J., Zhong, Y., Burcul, A., Mohan, P., Jiang, M., Sun, L., Yong-Gonzalez, V., Viale, A., Cross, J. R., Hendrickson, R. C., Rätsch, G., Ouyang, Z., Wendel, H.-G. Tags: Leukemia & Lymphoma, Tumor Immunology Articles Source Type: research

CD81 is a novel immunotherapeutic target for B cell lymphoma
The tetraspanin CD81 was initially discovered by screening mAbs elicited against a human B cell lymphoma for their direct antiproliferative effects. We now show that 5A6, one of the mAbs that target CD81, has therapeutic potential. This antibody inhibits the growth of B cell lymphoma in a xenograft model as effectively as rituximab, which is a standard treatment for B cell lymphoma. Importantly, unlike rituximab, which depletes normal as well as malignant B cells, 5A6 selectively kills human lymphoma cells from fresh biopsy specimens while sparing the normal lymphoid cells in the tumor microenvironment. The 5A6 antibody sh...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Vences-Catalan, F., Kuo, C.-C., Rajapaksa, R., Duault, C., Andor, N., Czerwinski, D. K., Levy, R., Levy, S. Tags: Leukemia & Lymphoma, Tumor Immunology Articles Source Type: research

Sphingosine-1-phosphate receptor 2 restrains egress of {gamma}{delta} T cells from the skin
Maintenance of a population of IL-17–committed T cells in the dermis is important in promoting tissue immunity. However, the signals facilitating T cell retention within the dermis remain poorly understood. Here, we find that sphingosine-1-phosphate receptor 2 (S1PR2) acts in a cell-intrinsic manner to oppose T cell migration from the dermis to the skin draining lymph node (dLN). Migration of dermal T cells to the dLN under steady-state conditions occurs in an S1PR1-dependent manner. S1PR1 and CD69 are reciprocally expressed on dermal T cells, with loss of CD69 associated with increased S1PR1 expression and enhanced ...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Laidlaw, B. J., Gray, E. E., Zhang, Y., Ramirez-Valle, F., Cyster, J. G. Tags: Mucosal Immunology Brief Definitive Reports Source Type: research

Cell death-mediated cytokine release and its therapeutic implications
Targeting apoptosis to treat diseases has seen tremendous success over the past decades. More recently, alternative forms of regulated cell death, including pyroptosis and necroptosis, have been described. Understanding the molecular cascades regulating both pyroptosis and necroptosis will yield even more targets to treat diseases. These lytic forms of cell death are distinct from apoptosis due to their characteristic lysis and release of cellular components that promote disease or direct a beneficial immune response. In this review, we focus on how pyroptosis and necroptosis, which release potent immune cytokines such as ...
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Place, D. E., Kanneganti, T.-D. Tags: Innate Immunity and Inflammation Review Source Type: research

Sarah-Maria Fendt: Driving scientific discovery through collaboration
Sarah-Maria Fendt is a principal investigator at the Flemish Institute for Biotechnology (VIB) in Belgium, and her laboratory focuses on cellular metabolism and metabolic regulation. Recent work from Sarah’s laboratory has shown that pyruvate available in the metastatic niche enables cancer cells to shape their environment and promote metastatic outgrowth. We contacted Sarah to find out more about her journey in science so far. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

c-Myc steers translation in lymphoma
Members of the MYC family of oncogenes are master regulators of mRNA translation. In this issue of JEM, Singh et al. (https://doi.org/10.1084/jem.20181726) demonstrate that c-Myc governs protein synthesis in lymphoma cells by interfering with SRSF1- and RBM42-mediated suppression of mRNA translation and by altering selection of translation initiation sites. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Cargnello, M., Topisirovic, I. Tags: Leukemia & Lymphoma, Metabolism Insights Source Type: research

CD81 as target for B cell lymphomas
In this issue of JEM, Vences-Catalán et al. (https://doi.org/10.1084/jem.20190186) demonstrate that a particular anti-CD81 antibody shows promising features as a novel immunotherapeutic tool to treat B cell lymphomas. Surprisingly, although CD81 is widely expressed, only minor side effects on other CD81+ immune cells analyzed were observed. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - June 30, 2019 Category: Internal Medicine Authors: Küppers, R. Tags: Leukemia & Lymphoma Insights Source Type: research

Development of immune checkpoint therapy for cancer
Since the early 20th century, immunologists have investigated mechanisms that protect vertebrates from damaging immune responses against self-antigens by mature lymphocytes, i.e., peripheral tolerance. These mechanisms have been increasingly delineated at the molecular level, ultimately culminating in new therapeutics that have revolutionized clinical oncology. Here, we describe basic science and clinical discoveries that converge mainly on two molecules, CTLA-4 and PD-1, that were recognized with the 2018 Nobel Prize in Physiology or Medicine awarded to James Allison and Tasuku Honjo. We discuss their investigations and t...
Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Fritz, J. M., Lenardo, M. J. Tags: Tumor Immunology, Tolerance Review Source Type: research