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MyD88 in T cells

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https://www.readbyqxmd.com/read/28817719/t-cell-expression-of-il-18r-and-dr3-is-essential-for-non-cognate-stimulation-of-th1-cells-and-optimal-clearance-of-intracellular-bacteria
#1
Oanh H Pham, Hope O'Donnell, Aymen Al-Shamkhani, Tobias Kerrinnes, Renée M Tsolis, Stephen J McSorley
Th1 cells can be activated by TCR-independent stimuli, but the importance of this pathway in vivo and the precise mechanisms involved require further investigation. Here, we used a simple model of non-cognate Th1 cell stimulation in Salmonella-infected mice to examine these issues. CD4 Th1 cell expression of both IL-18R and DR3 was required for optimal IFN-γ induction in response to non-cognate stimulation, while IL-15R expression was dispensable. Interestingly, effector Th1 cells generated by immunization rather than live infection had lower non-cognate activity despite comparable IL-18R and DR3 expression...
August 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28813659/the-dna-methylcytosine-dioxygenase-tet2-sustains-immunosuppressive-function-of-tumor-infiltrating-myeloid-cells-to-promote-melanoma-progression
#2
Wen Pan, Shu Zhu, Kun Qu, Katrina Meeth, Jijun Cheng, Kaixin He, Hongdi Ma, Yan Liao, Xizhi Wen, Christine Roden, Zuzana Tobiasova, Zheng Wei, Jun Zhao, Jun Liu, Ji Zheng, Bo Guo, Sajid A Khan, Marcus Bosenberg, Richard A Flavell, Jun Lu
Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function...
August 15, 2017: Immunity
https://www.readbyqxmd.com/read/28811957/mapping-the-human-t-cell-repertoire-to-recurrent-driver-mutations-in-myd88-and-ezh2-in-lymphoma
#3
Julie S Nielsen, Andrew R Chang, Darin A Wick, Colin G Sedgwick, Zusheng Zong, Andrew J Mungall, Spencer D Martin, Natalie N Kinloch, Susann Ott-Langer, Zabrina L Brumme, Steven P Treon, Joseph M Connors, Randy D Gascoyne, John R Webb, Brian R Berry, Ryan D Morin, Nicol Macpherson, Brad H Nelson
Oncogenic "driver" mutations are theoretically attractive targets for the immunotherapy of lymphoid cancers, yet the proportion that can be recognized by T cells remains poorly defined. To address this issue without any confounding effects of the patient's immune system, we assessed T cells from 19 healthy donors for recognition of three common driver mutations in lymphoma: MYD88(L265P), EZH2(Y641F) , and EZH2(Y641N) . Donors collectively expressed the 10 most prevalent HLA class I alleles, including HLA-A*02:01...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28804220/antitumor-macrophage-response-to-bacillus-pumilus-ribonuclease-binase
#4
Anna Makeeva, Julian Rodriguez-Montesinos, Pavel Zelenikhin, Alexander Nesmelov, Klaus T Preissner, Hector A Cabrera-Fuentes, Olga N Ilinskaya
Extracellular bacterial ribonucleases such as binase from Bacillus pumilus possess cytotoxic activity against tumor cells with a potential for clinical application. Moreover, they may induce activation of tumor-derived macrophages either into the M1-phenotype with well-documented functions in the regulation of the antitumor immune response or into M2-macrophages that may stimulate tumor growth, metastasis, and angiogenesis. In this study, binase or endogenous RNase1 (but not RNA or short oligonucleotides) stimulated the expression of activated NF-κB p65 subunit in macrophages...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28801306/inducible-activation-of-myd88-and-cd40-in-car-t-cells-results-in-controllable-and-potent-antitumor-activity-in-preclinical-solid-tumor-models
#5
Melinda Mata, Claudia Gerken, Phuong Nguyen, Giedre Krenciute, David M Spencer, Stephen Gottschalk
Adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CARs) has had limited success for solid tumors in early phase clinical studies. We reasoned that introducing into CAR T-cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T-cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ...
August 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28794025/retrovirus-based-virus-like-particle-immunogenicity-and-its-modulation-by-toll-like-receptor-activation
#6
Fabien Pitoiset, Thomas Vazquez, Beatrice Levacher, Djamel Nehar-Belaid, Nicolas Dérian, James Vigneron, David Klatzmann, Bertrand Bellier
Retrovirus-derived virus-like particles (VLPs) are particularly interesting vaccine platforms as they trigger efficient humoral and cellular immune responses and can be used to display heterologous antigens. In this study, we characterized the intrinsic immunogenicity of VLPs and investigated their possible adjuvantization by incorporation of toll-like receptor (TLR) ligands. We designed a non-coding single-stranded RNA (ncRNA) that could be encapsidated by VLPs and induce TLR7/8-signaling. We found that VLPs efficiently induce in vitro dendritic cell activation, which can be improved by ncRNA encapsidation (ncRNAVLPs)...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28762497/t-cell-dependent-antigen-adjuvanted-with-dotap-cpg-b-but-not-dotap-cpg-a-induces-robust-germinal-center-responses-and-high-affinity-antibodies-in-mice
#7
Munir Akkaya, Billur Akkaya, Patrick W Sheehan, Pietro Miozzo, Mirna Pena, Chen-Feng Qi, Javier Manzella-Lapeira, Silvia Bolland, Susan K Pierce
The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP...
August 1, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28757610/the-il-1r-tlr-signaling-pathway-is-essential-for-efficient-cd8-t-cell-responses-against-hepatitis-b-virus-in-the-hydrodynamic-injection-mouse-model
#8
Zhiyong Ma, Jia Liu, Weimin Wu, Ejuan Zhang, Xiaoyong Zhang, Qian Li, Gennadiy Zelinskyy, Jan Buer, Ulf Dittmer, Carsten J Kirschning, Mengji Lu
The outcome of hepatitis B viral (HBV) infection is determined by the complex interactions between replicating HBV and the immune system. While the role of the adaptive immune system in the resolution of HBV infection has been studied extensively, the contribution of innate immune mechanisms remains to be defined. Here we examined the role of the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling pathway in adaptive immune responses and viral clearance by exploring the HBV mouse model. Hydrodynamic injection with a replication-competent HBV genome was performed in wild-type mice (WT) and a panel of mouse strains lacking specific innate immunity component expression...
July 31, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28750349/escherichia-coli-maltose-binding-protein-mbp-activates-mouse-th1-through-tlr2-mediated-myd88-dependent-pathway-and-tlr4-mediated-trif-dependent-pathway
#9
GuoMu Liu, YiXin Zhang, NanNan Zhang, WeiHua Ni, Jing Jie, LiNa Jiang, GuiXiang Tai
MBP (maltose-binding protein) is a component of Escherichia coli. Our previous study found that MBP directly induces the activation of Th1 (T helper type 1), but the molecular mechanism remains unclear. In the present study, CD4(+)T cells were purified from the spleens of normal mice using antibody-coated immunomagnetic beads by negative selection. CD4(+)T cells activated with a CD3/CD28 antibody were stimulated with MBP. The results indicated that MBP elevated IFN-γ mRNA levels in activated CD4(+)T cells and promoted IFN-γ production from activated CD4(+)T cells...
July 24, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28733470/dendritic-cell-targeted-lentiviral-vector-immunization-uses-pseudotransduction-and-dna-mediated-sting-and-cgas-activation
#10
Jocelyn T Kim, Yarong Liu, Rajan P Kulkarni, Kevin K Lee, Bingbing Dai, Geoffrey Lovely, Yong Ouyang, Pin Wang, Lili Yang, David Baltimore
Dendritic cell (DC) activation and antigen presentation are critical for efficient priming of T cell responses. Here, we study how lentiviral vectors (LVs) deliver antigen and activate DCs to generate T cell immunization in vivo. We report that antigenic proteins delivered in vector particles via pseudotransduction were sufficient to stimulate an antigen-specific immune response. The delivery of the viral genome encoding the antigen increased the magnitude of this response in vivo but was irrelevant in vitro...
July 21, 2017: Science Immunology
https://www.readbyqxmd.com/read/28697888/regulated-expansion-and-survival-of-chimeric-antigen-receptor-modified-t-cells-using-small-molecule-dependent-inducible-myd88-cd40
#11
Aaron E Foster, Aruna Mahendravada, Nicholas P Shinners, Wei-Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L Shaw, Sunandan Saha, MyLinh T Duong, Matthew R Collinson-Pautz, David L Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J Henri Bayle, Kevin M Slawin, David M Spencer
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4(+) and CD8(+) T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function...
July 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28680375/tlr-myd88-mediated-innate-immunity-in-intestinal-graft-versus-host-disease
#12
REVIEW
Young-Kwan Lee, Myungsoo Kang, Eun Young Choi
Graft-versus-host disease (GHVD) is a severe complication after allogeneic hematopoietic stem cell transplantation. The degree of inflammation in the gastrointestinal tract, a major GVHD target organ, correlates with the disease severity. Intestinal inflammation is initiated by epithelial damage caused by pre-conditioning irradiation. In combination with damages caused by donor-derived T cells, such damage disrupts the epithelial barrier and exposes innate immune cells to pathogenic and commensal intestinal bacteria, which release ligands for Toll-like receptors (TLRs)...
June 2017: Immune Network
https://www.readbyqxmd.com/read/28679988/follicular-lymphoma-with-plasmacytic-differentiation-accompanied-by-monoclonal-igg-gammopathy
#13
Tomomi Oka, Masayuki Kobayashi, Takaya Komori, Hirokazu Nakamine, Toshiyuki Kitano, Masakatsu Hishizawa, Tadakazu Kondoh, Kouhei Yamashita, Akifumi Takaori-Kondo
A 59-year-old woman presented with high serum total protein, detected on a screening examination. Laboratory tests revealed high plasma levels of M-protein (IgG-λ), and FDG-PET/CT revealed systemic lymph node swelling and a large tumorous mass in the abdominal cavity. Bone marrow aspirates contained 8.4% plasma cells and approximately 30% abnormal small lymphocytes. A biopsy of the left supraclavicular lymph node was initially interpreted as lymphoplasmacytic lymphoma (LPL). However, chromosomal analysis of the lymph node demonstrated an unusual karyotype with t (14;18) (q32;q21)...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28659358/b-cell-extrinsic-myd88-and-fcer1g-negatively-regulate-autoreactive-and-normal-b-cell-immune-responses
#14
Rebecca A Sweet, Kevin M Nickerson, Jaime L Cullen, Yujuan Wang, Mark J Shlomchik
MyD88 and FcR common γ-chain (Fcer1g, FcRγ) elicit proinflammatory responses to exogenous Ags. Deletion of these receptors in autoimmune models has generally led to reduced overall disease. In B cells, Myd88 is required for anti-DNA and anti-RNA autoantibody responses, whereas Fcer1g is not expressed in these cells. The roles of these receptors in myeloid cells during B cell autoimmune activation remain less clear. To investigate the roles of Myd88 and Fcer1g in non-B cells, we transferred anti-self-IgG (rheumatoid factor) B cells and their physiologic target Ag, anti-chromatin Ab, into mice lacking Fcer1g, Myd88, or both and studied the extrafollicular plasmablast response...
August 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28655469/transcutaneous-immunization-with-a-novel-imiquimod-nanoemulsion-induces-superior-t-cell-responses-and-virus-protection
#15
Pamela Aranda Lopez, Mark Denny, Ann-Kathrin Hartmann, Astrid Alflen, Hans Christian Probst, Esther von Stebut, Stefan Tenzer, Hansjörg Schild, Michael Stassen, Peter Langguth, Markus P Radsak
BACKGROUND: Transcutaneous immunization (TCI) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. TCI using a cytotoxic T lymphocyte (CTL) epitope and the Toll-like receptor 7 (TLR7) agonist imiquimod mounts strong CTL responses by activation and maturation of skin-derived dendritic cells (DCs) and their migration to lymph nodes. However, TCI based on the commercial formulation Aldara only induces transient CTL responses that needs further improvement for the induction of durable therapeutic immune responses...
June 16, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28642279/role-of-myd88-signaling-in-the-imiquimod-induced-mouse-model-of-psoriasis-focus-on-innate-myeloid-cells
#16
Sara Costa, Olivia Marini, Dalila Bevilacqua, Anthony L DeFranco, Baidong Hou, Silvia Lonardi, William Vermi, Pamela Rodegher, Anna Panato, Franco Tagliaro, Clifford A Lowell, Marco A Cassatella, Giampiero Girolomoni, Patrizia Scapini
Psoriasis is a chronic skin disease associated with deregulated activation of immune cells and keratinocytes. In this study, we used the imiquimod (IMQ)-induced mouse model of psoriasis to dissect better the contribution of hematopoietic and skin-resident stromal cells to psoriasis development. The comparison of disease development in mice carrying the hematopoietic cell-specific deletion of MyD88 (Myd88(fl/fl)Vav-cre(+) mice) with mice carrying the total MyD88 deficiency (Myd88(-/-) mice), we show that the progression of skin and systemic inflammation, as well as of epidermal thickening, was completely dependent on MyD88 expression in hematopoietic cells...
June 22, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28611775/inhibition-of-myeloid-differentiation-factor-88-reduces-human-and-mouse-t-cell-interleukin-17-and-ifn%C3%AE-production-and-ameliorates-experimental-autoimmune-encephalomyelitis-induced-in-mice
#17
Shira Dishon, Shmuel J Cohen, Irun R Cohen, Gabriel Nussbaum
Myeloid differentiation factor 88 (MyD88) recruits signaling proteins to the intracellular domain of receptors belonging to the toll-like/interleukin-1 (IL-1) receptor superfamily. Mice lacking MyD88 are highly susceptible to infectious diseases, but tend to resist experimentally induced autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and manifest diminished allograft rejection. We reasoned that inhibition of MyD88 should influence the cytokine profile of responding T cells by blocking costimulatory molecule expression by antigen-presenting cells (APCs) and by inhibiting T-cell responses to IL-18...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28599094/rational-design-of-peptide-derivatives-for-inhibition-of-myd88-mediated-tlr-signaling-in-human-pbmcs-and-epithelial-cells-exposed-to-f-tularensis
#18
D A Ryan, M Degardin, S Alam, T L Kissner, M Hale, M D Cameron, M Rebek, D Ajami, K U Saikh, J Rebek
Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88-mediated TLR signaling by F. tularensis. Fifty-three tripeptide derivatives were synthesized to mimic a key BB-loop region involved in toll-like/interleukin-1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF-α, IFN-γ, IL-6, and IL-1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F...
June 9, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28550425/cpg-oligonucleotide-mediated-co-stimulation-of-mouse-invariant-natural-killer-t-cells-negatively-regulates-their-activation-status
#19
Raveendra R Kulkarni, Alexander Ian Villanueva, Leah R Read, Jennifer T Brisbin, Siddhartha Kumar Bhaumik, Jonathan LaMarre, Kaja Murali-Krishna, Shayan Sharif
Invariant natural killer T (iNKT) cells play important roles in antimicrobial defense and immune-regulation. We have previously shown that iNKT cells express certain toll-like receptors (TLR), and that TLR co-stimulation of iNKT cells in the presence of suboptimal concentrations of T cell receptor (TCR) agonists enhances cellular activation. In the present study, we investigated the regulatory effects of CpG oligonucleotides in mouse primary hepatic and splenic iNKT cells and in DN32.D3 iNKT cells. We show that CpG treatment of iNKT cells in the presence of higher concentrations of TCR agonists (α-GalCer or anti-CD3 mAb) results in the up-regulation of TLR9 in iNKT cells with a concurrent reduction in their cellular activation, as assessed by their production of IL-2, IL-4 and IFN-γ compared with controls...
May 27, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28534936/forsythoside-a-exerts-an-anti-endotoxin-effect-by-blocking-the-lps-tlr4-signaling-pathway-and-inhibiting-tregs-in-vitro
#20
Xiao-Yan Zeng, Wei Yuan, Lin Zhou, Shi-Xiu Wang, Yong Xie, Ying-Jun Fu
Endotoxins, also referred to as lipopolysaccharides (LPS), are powerful immunostimulators involved in a number of severe diseases. Forsythoside A (FTA), a monomer of phenethyl alcohol glycosides extracted from Forsythia suspensa, has been shown to possess anti-bacterial and immunomodulatory properties. However, it is currently not known whether FTA can counter the adverse effects of endotoxins. We investigated the effect of FTA on LPS-stimulated RAW264.7 cells and primary lymphocytes to determine its molecular mechanism of action...
May 15, 2017: International Journal of Molecular Medicine
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