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Immunity

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https://www.readbyqxmd.com/read/29752063/proteomic-analyses-of-human-regulatory-t-cells-reveal-adaptations-in-signaling-pathways-that-protect-cellular-identity
#1
Eloy Cuadrado, Maartje van den Biggelaar, Sander de Kivit, Yi-Yen Chen, Manon Slot, Ihsane Doubal, Alexander Meijer, Rene A W van Lier, Jannie Borst, Derk Amsen
To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways...
May 5, 2018: Immunity
https://www.readbyqxmd.com/read/29752066/the-microglial-innate-immune-receptor-trem2-is-required-for-synapse-elimination-and-normal-brain-connectivity
#2
Fabia Filipello, Raffaella Morini, Irene Corradini, Valerio Zerbi, Alice Canzi, Bernadeta Michalski, Marco Erreni, Marija Markicevic, Chiara Starvaggi-Cucuzza, Karel Otero, Laura Piccio, Francesca Cignarella, Fabio Perrucci, Matteo Tamborini, Marco Genua, Lawrence Rajendran, Elisabetta Menna, Stefania Vetrano, Margaret Fahnestock, Rosa Chiara Paolicelli, Michela Matteoli
The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development...
May 3, 2018: Immunity
https://www.readbyqxmd.com/read/29752064/cell-specific-imd-nf-%C3%AE%C2%BAb-responses-enable-simultaneous-antibacterial-immunity-and-intestinal-epithelial-cell-shedding-upon-bacterial-infection
#3
Zongzhao Zhai, Jean-Philippe Boquete, Bruno Lemaitre
Intestinal infection triggers potent immune responses to combat pathogens and concomitantly drives epithelial renewal to maintain barrier integrity. Current models propose that epithelial renewal is primarily driven by damage caused by reactive oxygen species (ROS). Here we found that in Drosophila, the Imd-NF-κB pathway controlled enterocyte (EC) shedding upon infection, via a mechanism independent of ROS-associated apoptosis. Mechanistically, the Imd pathway synergized with JNK signaling to induce epithelial cell shedding specifically in the context of bacterial infection, requiring also the reduced expression of the transcription factor GATAe...
May 3, 2018: Immunity
https://www.readbyqxmd.com/read/29752065/cd36-mediates-cell-surface-antigens-to-promote-thymic-development-of-the-regulatory-t-cell-receptor-repertoire-and-allo-tolerance
#4
Justin S A Perry, Emilie V Russler-Germain, You W Zhou, Whitney Purtha, Matthew L Cooper, Jaebok Choi, Mark A Schroeder, Vanessa Salazar, Takeshi Egawa, Byeong-Chel Lee, Nada A Abumrad, Brian S Kim, Mark S Anderson, John F DiPersio, Chyi-Song Hsieh
The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens...
April 30, 2018: Immunity
https://www.readbyqxmd.com/read/29752062/single-cell-rna-sequencing-of-lymph-node-stromal-cells-reveals-niche-associated-heterogeneity
#5
Lauren B Rodda, Erick Lu, Mariko L Bennett, Caroline L Sokol, Xiaoming Wang, Sanjiv A Luther, Ben A Barres, Andrew D Luster, Chun Jimmie Ye, Jason G Cyster
Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol-25-hydroxylase+ cells located at the T-zone perimeter, Cxcl9+ TRCs in the T-zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches...
April 26, 2018: Immunity
https://www.readbyqxmd.com/read/29653697/an-interleukin-25-mediated-autoregulatory-circuit-in-keratinocytes-plays-a-pivotal-role-in-psoriatic-skin-inflammation
#6
Miao Xu, Huiping Lu, Young-Hee Lee, Yelin Wu, Kewei Liu, Yuling Shi, Haoran An, Jingren Zhang, Xiaohu Wang, Yuping Lai, Chen Dong
Psoriasis is a chronic autoinflammatory skin disease. Although interleukin-17, derived from lymphocytes, has been shown to be critical in psoriasis, the initiation and maintenance of chronic skin inflammation has not been well understood. IL-25 (also called IL-17E), another IL-17 family cytokine, is well known to regulate allergic responses and type 2 immunity. Here we have shown that IL-25, also highly expressed in the lesional skin of psoriasis patients, was regulated by IL-17 in murine skin of a imiquimod (IMQ)-induced psoriasis model...
April 9, 2018: Immunity
https://www.readbyqxmd.com/read/29653696/manganese-increases-the-sensitivity-of-the-cgas-sting-pathway-for-double-stranded-dna-and-is-required-for-the-host-defense-against-dna-viruses
#7
Chenguang Wang, Yukun Guan, Mengze Lv, Rui Zhang, Zhaoying Guo, Xiaoming Wei, Xiaoxia Du, Jing Yang, Tong Li, Yi Wan, Xiaodong Su, Xiaojun Huang, Zhengfan Jiang
Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn2+ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn2+ was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn2+ enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory...
April 5, 2018: Immunity
https://www.readbyqxmd.com/read/29628290/the-immune-landscape-of-cancer
#8
Vésteinn Thorsson, David L Gibbs, Scott D Brown, Denise Wolf, Dante S Bortone, Tai-Hsien Ou Yang, Eduard Porta-Pardo, Galen F Gao, Christopher L Plaisier, James A Eddy, Elad Ziv, Aedin C Culhane, Evan O Paull, I K Ashok Sivakumar, Andrew J Gentles, Raunaq Malhotra, Farshad Farshidfar, Antonio Colaprico, Joel S Parker, Lisle E Mose, Nam Sy Vo, Jianfang Liu, Yuexin Liu, Janet Rader, Varsha Dhankani, Sheila M Reynolds, Reanne Bowlby, Andrea Califano, Andrew D Cherniack, Dimitris Anastassiou, Davide Bedognetti, Arvind Rao, Ken Chen, Alexander Krasnitz, Hai Hu, Tathiane M Malta, Houtan Noushmehr, Chandra Sekhar Pedamallu, Susan Bullman, Akinyemi I Ojesina, Andrew Lamb, Wanding Zhou, Hui Shen, Toni K Choueiri, John N Weinstein, Justin Guinney, Joel Saltz, Robert A Holt, Charles E Rabkin, Alexander J Lazar, Jonathan S Serody, Elizabeth G Demicco, Mary L Disis, Benjamin G Vincent, Llya Shmulevich
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis...
April 4, 2018: Immunity
https://www.readbyqxmd.com/read/29625895/klrg1-effector-cd8-t-cells-lose-klrg1-differentiate-into-all-memory-t-cell-lineages-and-convey-enhanced-protective-immunity
#9
Dietmar Herndler-Brandstetter, Harumichi Ishigame, Ryo Shinnakasu, Valerie Plajer, Carmen Stecher, Jun Zhao, Melanie Lietzenmayer, Lina Kroehling, Akiko Takumi, Kohei Kometani, Takeshi Inoue, Yuval Kluger, Susan M Kaech, Tomohiro Kurosaki, Takaharu Okada, Richard A Flavell
Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in a Bach2-dependent manner and differentiated into all memory T cell linages, including CX3 CR1int peripheral memory cells and tissue-resident memory cells...
March 31, 2018: Immunity
https://www.readbyqxmd.com/read/29625897/a-circular-rna-protects-dormant-hematopoietic-stem-cells-from-dna-sensor-cgas-mediated-exhaustion
#10
Pengyan Xia, Shuo Wang, Buqing Ye, Ying Du, Chong Li, Zhen Xiong, Yuan Qu, Zusen Fan
Disrupting the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how HSCs sustain their quiescent state and avoid type I interferon (IFN)-mediated exhaustion remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly expressed in the nucleus of long-term (LT)-HSCs. Cia-cGAS deficiency in mice caused elevated expression of type I IFNs in bone marrow and led to decreased numbers of dormant LT-HSCs...
March 29, 2018: Immunity
https://www.readbyqxmd.com/read/29625896/co-inhibitory-molecule-b7-superfamily-member-1-expressed-by-tumor-infiltrating-myeloid-cells-induces-dysfunction-of-anti-tumor-cd8-t-cells
#11
Jing Li, Younghee Lee, Yanjian Li, Yu Jiang, Huiping Lu, Wenjuan Zang, Xiaohong Zhao, Liguo Liu, Yang Chen, Haidong Tan, Zhiying Yang, Michael Q Zhang, Tak W Mak, Ling Ni, Chen Dong
The molecular mechanisms whereby CD8+ T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction...
March 29, 2018: Immunity
https://www.readbyqxmd.com/read/29625894/toll-like-receptor-9-contains-two-dna-binding-sites-that-function-cooperatively-to-promote-receptor-dimerization-and-activation
#12
Umeharu Ohto, Hanako Ishida, Takuma Shibata, Ryota Sato, Kensuke Miyake, Toshiyuki Shimizu
Toll-like receptor 9 (TLR9) recognizes DNA containing CpG motifs derived from bacteria and viruses and activates the innate immune response to eliminate them. TLR9 is known to bind to CpG DNA, and here, we identified another DNA binding site in TLR9 that binds DNA containing cytosine at the second position from the 5' end (5'-xCx DNA). 5'-xCx DNAs bound to TLR9 in the presence of CpG DNA and cooperatively promoted dimerization and activation of TLR9. Binding at both sites was important for efficient activation of TLR9...
March 24, 2018: Immunity
https://www.readbyqxmd.com/read/29625893/interleukin-15-complex-treatment-protects-mice-from-cerebral-malaria-by-inducing-interleukin-10-producing-natural-killer-cells
#13
Kristina S Burrack, Matthew A Huggins, Emily Taras, Philip Dougherty, Christine M Henzler, Rendong Yang, Sarah Alter, Emily K Jeng, Hing C Wong, Martin Felices, Frank Cichocki, Jeffrey S Miller, Geoffrey T Hart, Aaron J Johnson, Stephen C Jameson, Sara E Hamilton
Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM...
March 20, 2018: Immunity
https://www.readbyqxmd.com/read/29768180/dietary-fiber-confers-protection-against-flu-by-shaping-ly6c-patrolling-monocyte-hematopoiesis-and-cd8-t-cell-metabolism
#14
Aurélien Trompette, Eva S Gollwitzer, Céline Pattaroni, Isabel C Lopez-Mejia, Erika Riva, Julie Pernot, Niki Ubags, Lluis Fajas, Laurent P Nicod, Benjamin J Marsland
Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c- patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768179/intestinal-epithelial-wnt-signaling-mediates-acetylcholine-triggered-host-defense-against-infection
#15
Sid Ahmed Labed, Khursheed A Wani, Sakthimala Jagadeesan, Abdul Hakkim, Mehran Najibi, Javier Elbio Irazoqui
Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768178/trained-memory-of-human-uterine-nk-cells-enhances-their-function-in-subsequent-pregnancies
#16
Moriya Gamliel, Debra Goldman-Wohl, Batya Isaacson, Chamutal Gur, Natan Stein, Rachel Yamin, Michael Berger, Myriam Grunewald, Eli Keshet, Yoach Rais, Chamutal Bornstein, Eyal David, Adam Jelinski, Iris Eisenberg, Caryn Greenfield, Arbel Ben-David, Tal Imbar, Ronit Gilad, Ronit Haimov-Kochman, David Mankuta, Matan Elami-Suzin, Ido Amit, Jacob H Hanna, Simcha Yagel, Ofer Mandelboim
Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs)...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768177/expression-of-the-dna-binding-factor-tox-promotes-the-encephalitogenic-potential-of-microbe-induced-autoreactive-cd8-t-cells
#17
Nicolas Page, Bogna Klimek, Mathias De Roo, Karin Steinbach, Hadrien Soldati, Sylvain Lemeille, Ingrid Wagner, Mario Kreutzfeldt, Giovanni Di Liberto, Ilena Vincenti, Thomas Lingner, Gabriela Salinas, Wolfgang Brück, Mikael Simons, Rabih Murr, Jonathan Kaye, Dietmar Zehn, Daniel D Pinschewer, Doron Merkler
Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768176/the-chaperone-unc93b1-regulates-toll-like-receptor-stability-independently-of-endosomal-tlr-transport
#18
Karin Pelka, Damien Bertheloot, Elisa Reimer, Kshiti Phulphagar, Susanne V Schmidt, Anette Christ, Rainer Stahl, Nicki Watson, Kensuke Miyake, Nir Hacohen, Albert Haas, Melanie M Brinkmann, Ann Marshak-Rothstein, Felix Meissner, Eicke Latz
Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768175/targeting-the-latent-reservoir-for-hiv-1
#19
REVIEW
Srona Sengupta, Robert F Siliciano
Antiretroviral therapy can effectively block HIV-1 replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to a cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768174/hiv-1-vaccines-based-on-antibody-identification-b-cell-ontogeny-and-epitope-structure
#20
REVIEW
Peter D Kwong, John R Mascola
HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion-closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design...
May 15, 2018: Immunity
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