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https://www.readbyqxmd.com/read/28811651/inkt-cells-prevent-obesity-induced-hepatic-steatosis-in-mice-in-a-c-c-chemokine-receptor-7-dependent-manner
#1
H M Kim, R Lee, E S Lee, M H Kwon, J H Huh, B-E Kwon, E-K Park, S-Y Chang, M-N Kweon, P-H Kim, H-J Ko, C H Chung
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease, and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism...
August 16, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28783690/cross-talk-between-inkt-cells-and-monocytes-triggers-an-atheroprotective-immune-response-in-sle-patients-with-asymptomatic-plaque
#2
Edward Smith, Sara Croca, Kirsty E Waddington, Reecha Sofat, Maura Griffin, Andrew Nicolaides, David A Isenberg, Ines Pineda Torra, Anisur Rahman, Elizabeth C Jury
Accelerated atherosclerosis is a complication of the autoimmune rheumatic disease systemic lupus erythematosus (SLE). We questioned the role played by invariant natural killer T (iNKT) cells in this process because they not only are defective in autoimmunity but also promote atherosclerosis in response to CD1d-mediated lipid antigen presentation. iNKT cells from SLE patients with asymptomatic plaque (SLE-P) had increased proliferation and interleukin-4 production compared with those from SLE patients with no plaque...
December 2, 2016: Science Immunology
https://www.readbyqxmd.com/read/28780376/retinoic-acid-induction-of-cd1d-expression-primes-chronic-lymphocytic-leukemia-b-cells-for-killing-by-cd8-invariant-natural-killer-t-cells
#3
Yasmeen G Ghnewa, Vincent P O'Reilly, Elisabeth Vandenberghe, Paul V Browne, Anthony M McElligott, Derek G Doherty
Invariant natural killer T (iNKT) cells are cytotoxic T cells that respond to glycolipid antigens presented by CD1d. Therapeutic activation of iNKT cells with α-galactosylceramide (α-GalCer) can prevent and reverse tumor growth in mice and clinical trials involving α-GalCer-stimulated iNKT cells are ongoing in humans. B cells express CD1d, however, we show that CD1d expression is reduced on B cells from patients with chronic lymphocytic leukemia (CLL). B cells from CLL patients pulsed with α-GalCer failed to stimulate cytolytic degranulation by iNKT cell lines, but could present the more potent glycolipid analogue, 7DW8-5...
August 3, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28766890/inkt-cell-activation-plus-t-cell-transfer-establishes-complete-chimerism-in-a-murine-sublethal-bone-marrow-transplant-model
#4
Rumi Ishii, Toshihito Hirai, Satoshi Miyairi, Kazuya Omoto, Masayoshi Okumi, Yasuyuki Ishii, Kazunari Tanabe
Transplant tolerance induction makes it possible to preserve functional grafts for a lifetime without immunosuppressants. One powerful method is to generate mixed hematopoietic chimeras in recipients by adoptive transfer of donor-derived bone marrow cells (BMCs). In our murine transplantation model, we established a novel method for mixed chimera generation using sublethal irradiation, CD40-CD40L blockade, and invariant natural killer T-cell activation. However, numerous BMCs that are required to achieve stable chimerism makes it difficult to apply this model for human transplantation...
August 2, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28765611/the-differentiation-of-ror-%C3%AE-t-expressing-inkt17-cells-is-orchestrated-by-runx1
#5
Puspa Thapa, Bryce Manso, Ji Young Chung, Sinibaldo Romera Arocha, Hai-Hui Xue, Derek B Sant' Angelo, Virginia Smith Shapiro
iNKT cells are a unique lineage of T cells that recognize glycolipid presented by CD1d. In the thymus, they differentiate into iNKT1, iNKT2 and iNKT17 effector subsets, characterized by preferential expression of Tbet, Gata3 and ROR-γt and production of IFN-γ, IL-4 and IL-17, respectively. We demonstrate that the transcriptional regulator Runx1 is essential for the generation of ROR-γt expressing iNKT17 cells. PLZF-cre Runx1 cKO mice lack iNKT17 cells in the thymus, spleen and liver. Runx1-deficient iNKT cells have altered expression of several genes important for iNKT17 differentiation, including decreased expression of IL-7Rα, BATF and c-Maf and increased expression of Bcl11b and Lef1...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28761130/lipodystrophy-and-obesity-are-associated-with-decreased-number-of-t-cells-with-regulatory-function-and-pro-inflammatory-macrophage-phenotype
#6
S Berger, G Ceccarini, G Scabia, I Barone, C Pelosini, F Ferrari, S Magno, A Dattilo, L Chiovato, P Vitti, F Santini, M Maffei
BACKGROUND/OBJECTIVES: In lipodystrophy (LD) adipose tissue function to store lipids is impaired, leading to metabolic syndrome, similar to that found in obesity. Emerging evidence links dysmetabolism with disorders of the immune system. Our aim is to investigate whether T-cell populations with regulatory function and monocyte-derived macrophages (MDMs) are affected by LD and obesity. SUBJECTS/METHODS: Blood was collected from 16 LD, 16 obese (OB, BMI>30 kg m(-2)) and 16 healthy normal-weight women (CNT)...
July 10, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28758901/stromal-cell-cadherin-11-regulates-adipose-tissue-inflammation-and-diabetes
#7
Sook Kyung Chang, Ayano C Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J Wolf, Kevin Wei, Pui Y Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S Banks, Michael B Brenner
M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28751426/parp2-deficiency-affects-invariant-nkt-cell-maturation-and-protects-mice-from-concanavalin-a-induced-liver-injury
#8
Aveline Filliol, Claire Piquet-Pellorce, Sarah Dion, Valentine Genet, Catherine Lucas-Clerc, Françoise Dantzer, Michel Samson
Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during Concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells which promote inflammation and induce hepatocyte death, mediated by the activated invariant NKT-(iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs such as spleen, thymus, and bone marrow in Parp2 deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis...
July 27, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28743554/solubilization-of-%C3%AE-galactosylceramide-in-aqueous-medium-impact-on-natural-killer-t-cell-activation-and-antitumor-responses
#9
Elodie Macho-Fernandez, Neila Chekkat, Christophe Ehret, Jean-Sébastien Thomann, Marcella De Giorgi, Maria Vittoria Spanedda, Line Bourel-Bonnet, Didier Betbeder, Béatrice Heurtault, Christelle Faveeuw, Sylvie Fournel, Benoît Frisch, François Trottein
The potent antitumor effect of α-galactosylceramide (α-GalCer) is based on its recognition by invariant Natural Killer T cells (iNKT) after its capture and presentation by antigen presenting cells including dendritic cells (DCs). Synthetic α-GalCer has already been tested in advanced cancer patients but no or only moderate clinical responses were obtained. To optimize α-GalCer efficacy, we have postulated that alternative formulations impacting its molecular organization in aqueous medium could modify DC uptake and iNKT-based immune responses...
July 22, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28724935/histone-deacetylase-3-is-required-for-inkt-cell-development
#10
Puspa Thapa, Sinibaldo Romero Arocha, Ji Young Chung, Derek B Sant'Angelo, Virginia Smith Shapiro
NKT cells are a distinct subset that have developmental requirements that often differ from conventional T cells. Here, we show that NKT-specific deletion of Hdac3 results in a severe reduction in the number of iNKT cells, particularly of NKT1 cells. In addition, there is decreased cytokine production by Hdac3-deficient NKT2 and NKT17 cells. Hdac3-deficient iNKT cells have increased cell death that is not rescued by transgenic expression of Bcl-2 or Bcl-xL. Hdac3-deficient iNKT cells have less Cyto-ID staining and lower LC3A/B expression, indicative of reduced autophagy...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723564/the-lysine-acetyltransferase-gcn5-is-required-for-inkt-cell-development-through-egr2-acetylation
#11
Yajun Wang, Chawon Yun, Beixue Gao, Yuanming Xu, Yana Zhang, Yiming Wang, Qingfei Kong, Fang Zhao, Chyung-Ru Wang, Sharon Y R Dent, Jian Wang, Xiangping Xu, Hua-Bin Li, Deyu Fang
The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner...
July 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28716901/structural-determination-of-lipid-antigens-captured-at-the-cd1d-t-cell-receptor-interface
#12
Patrick J Brennan, Tan-Yun Cheng, Daniel G Pellicci, Gerald F M Watts, Natacha Veerapen, David C Young, Jamie Rossjohn, Gurdyal S Besra, Dale I Godfrey, Michael B Brenner, D Branch Moody
Glycolipid antigens recognized by αβ T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with α-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual α-anomeric linkage has been thought to define a "foreign" lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation...
August 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28698642/progressive-changes-in-cxcr4-expression-that-define-thymocyte-positive-selection-are-dispensable-for-both-innate-and-conventional-%C3%AE-%C3%AE-t-cell-development
#13
Beth Lucas, Andrea J White, Sonia M Parnell, Peter M Henley, William E Jenkinson, Graham Anderson
The ordered migration of immature thymocytes through thymic microenvironments generates both adaptive MHC restricted αβT-cells and innate CD1d-restricted iNKT-cells. While several chemokine receptors and ligands control multiple stages of this process, their involvement during early thymocyte development often precludes direct analysis of potential roles during later developmental stages. For example, because of early lethality of CXCR4(-/-) mice, and stage-specific requirements for CXCR4 in thymus colonisation and pre-TCR mediated selection, its role in thymic positive selection is unclear...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28694168/characterizing-porcine-invariant-natural-killer-t-cells-a-comparative-study-with-nk-cells-and-t-cells
#14
Guan Yang, Bianca L Artiaga, Sarah T Lewis, John P Driver
CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T cells that share phenotypic characteristics of both NK and conventional T cells (Tconv). Although iNKT cells have been well characterized in mice and humans, functional CD1d and CD1d-restricted iNKT cells are not universally expressed in mammals. Swine express iNKT cells that can be detected using α-galactosylceramide (α-GalCer)-loaded CD1d tetramers. In the present study, we characterized iNKT cells from the blood, spleen, lymph node, lung and liver of commercial mixed-breed pigs, and compared their phenotype to NK cells and Tconv...
July 8, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28685970/invariant-natural-killer-cells-change-after-an-oral-allergy-desensitization-protocol-for-cow-s-milk
#15
Antonella Cianferoni, Rushani Saltzman, Francesca Saretta, Simona Barni, Emily Dudek, Mary Kelleher, Jonathan M Spergel
BACKGROUND: Cow milk (CM) allergy (CMA) affects up to 3% of the pediatric population and recent data suggest that only about 50% will outgrow by age 8. Oral immunotherapy (OIT) is a type of immune-modulating treatment that is able to induce desensitization to food allergens, to increase tolerance threshold, to reduce the risk of anaphylaxis, and to improve the patient's quality of life. The examination of the immunological changes observed during the establishment of food allergy (FA) desensitization in FA patients is a window into the pathogenesis of food allergy and food tolerance development...
July 7, 2017: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28674535/leishmania-infantum-exoproducts-inhibit-human-invariant-nkt-cell-expansion-and-activation
#16
Renata Belo, Nuno Santarém, Cátia Pereira, Begoña Pérez-Cabezas, Fátima Macedo, Maria Leite-de-Moraes, Anabela Cordeiro-da-Silva
Leishmania infantum is one of the major parasite species associated with visceral leishmaniasis, a severe form of the disease that can become lethal if untreated. This obligate intracellular parasite has developed diverse strategies to escape the host immune response, such as exoproducts (Exo) carrying a wide range of molecules, including parasite virulence factors, which are potentially implicated in early stages of infection. Herein, we report that L. infantum Exo and its two fractions composed of extracellular vesicles (EVs) and vesicle-depleted-exoproducts (VDEs) inhibit human peripheral blood invariant natural killer T (iNKT) cell expansion in response to their specific ligand, the glycolipid α-GalactosylCeramide (α-GalCer), as well as their capacity to promptly produce IL-4 and IFNγ...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28655912/galactosylsphingamides-new-%C3%AE-galcer-analogues-to-probe-the-f-pocket-of-cd1d
#17
Joren Guillaume, Jing Wang, Jonas Janssens, Soumya G Remesh, Martijn D P Risseeuw, Tine Decruy, Mathy Froeyen, Dirk Elewaut, Dirk M Zajonc, Serge Van Calenbergh
Invariant Natural Killer T-cells (iNKT-cells) are an attractive target for immune response modulation, as upon CD1d-mediated stimulation with KRN7000, a synthetic α-galactosylceramide, they produce a vast amount of cytokines. Here we present a synthesis that allows swift modification of the phytosphingosine side chain by amidation of an advanced methyl ester precursor. The resulting KRN7000 derivatives, termed α-galactosylsphingamides, were evaluated for their capacity to stimulate iNKT-cells. While introduction of the amide-motif in the phytosphingosine chain is tolerated for CD1d binding and TCR recognition, the studied α-galactosylsphingamides showed compromised antigenic properties...
June 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#18
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28626526/efficient-divergent-synthesis-of-new-immunostimulant-4%C3%A2-modified-%C3%AE-galactosylceramide-analogues
#19
Jonas Janssens, Tine Decruy, Koen Venken, Toshiyuki Seki, Simon Krols, Johan Van der Eycken, Moriya Tsuji, Dirk Elewaut, Serge Van Calenbergh
A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a p-methoxybenzylidene (PMP) acetal to regioselectively liberate the 4″-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T-cells (iNKT) in vitro and in vivo...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28618148/mechanisms-underlying-induction-of-allergic-sensitization-by-pru-p-3
#20
L Tordesillas, N Cubells-Baeza, C Gómez-Casado, C Berin, V Esteban, W Barcik, L O'Mahony, C Ramirez, L F Pacios, M Garrido-Arandia, A Díaz-Perales
BACKGROUND: Recently, the nature of the lipid-ligand of Pru p 3, one of the most common plant food allergens in southern Europe, has been identified as a derivative of the alkaloid camptothecin bound to phytosphingosine. However, the origin of its immunological activity is still unknown. OBJECTIVE: We sought to evaluate the role of the Pru p 3 lipid-ligand in the immunogenic activity of Pru p 3. METHODS: In vitro cultures of different cell types (monocyte-derived dendritic cells [moDCs], PBMCs [peripheral blood mononuclear cells] and epithelial and iNKT-hybridoma cell lines) have been used to determine the immunological capacity of the ligand, by measuring cell proliferation, maturation markers and cytokine production...
June 15, 2017: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
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