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MyD88 in T cells

Matthew R Collinson-Pautz, Kevin M Slawin, Jonathan M Levitt, David M Spencer
Therapeutic DNA-based vaccines aim to prime an adaptive host immune response against tumor-associated antigens, eliminating cancer cells primarily through CD8+ cytotoxic T cell-mediated destruction. To be optimally effective, immunological adjuvants are required for the activation of tumor-specific CD8+ T cells responses by DNA vaccination. Here, we describe enhanced anti-tumor efficacy of an in vivo electroporation-delivered DNA vaccine by inclusion of a genetically encoded chimeric MyD88/CD40 (MC) adjuvant, which integrates both innate and adaptive immune signaling pathways...
2016: PloS One
H Zhang, Y-L Ye, M-X Li, S-B Ye, W-R Huang, T-T Cai, J He, J-Y Peng, T-H Duan, J Cui, X-S Zhang, F-J Zhou, R-F Wang, J Li
The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33(+) MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0...
October 10, 2016: Oncogene
Weihua Ni, Fang Wang, Guomu Liu, Nannan Zhang, Hongyan Yuan, Jing Jie, Guixiang Tai
Our previous study demonstrated that maltose-binding protein (MBP) combined with BCG induced synergistic mouse Th1 activation in vivo. Here, to explore the mechanism of MBP combined with BCG on Th1 activation, mouse purified CD4(+) T cells were stimulated with MBP and BCG in vitro. The results showed that MBP combined with BCG synergistically increased IFN-γ production, accompanied with the upregulation of TLR2/9 expressions, suggesting that TLR2/9 were involved in the combination-induced Th1 activation. Next, TLR2 antibodies and TLR9 inhibitor were used to further analyze the effects of TLRs in Th1 activation...
September 28, 2016: Molecular Immunology
Kyoung-Ho Pyo, You-Won Lee, Sun Min Lim, Eun-Hee Shin
Profilin-like protein in Toxoplasma gondii (TgPLP) is a Toll-like receptor (TLR) agonist. In this study, we investigated whether TgPLP has an adjuvant effect on immune function in autologous whole-tumor-cell vaccine (AWV) treatment. Mice vaccinated with AWV together with recombinant TgPLP protein had smaller CT26 tumors and increased survival. TgPLP treatment strongly increased the production of IL-12 through MyD88 signaling and several chemokines, including CCL5, CCL12, and XCL1, in bone marrow-derived macrophages (BMMs)...
September 28, 2016: Oncotarget
Hongmei Wang, Xusheng Zhang, Xiufen Zheng, Zhu Lan, Jun Shi, Jifu Jiang, Terry Zwiep, Qing Li, Douglas Quan, Zhu-Xu Zhang, Weiping Min
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart...
2016: Scientific Reports
A A Anas, J Yang, J Daan de Boer, J J T H Roelofs, B Hou, A F de Vos, T van der Poll
Asthma is a highly prevalent chronic allergic inflammatory disease of the airways affecting people worldwide. House dust mite (HDM) is the most common allergen implicated in human allergic asthma. HDM-induced allergic responses are thought to depend upon activation of pathways involving Toll-like receptors and their adaptor protein myeloid differentiation factor 88 (MyD88). We sought here to determine the role of MyD88 in myeloid and type II lung epithelial cells in the development of asthma-like allergic disease using a mouse model...
September 14, 2016: Clinical and Experimental Immunology
Cameron G McCarthy, Camilla F Wenceslau, Styliani Goulopoulou, Babak Baban, Takayuki Matsumoto, R Clinton Webb
BACKGROUND: Innate immune system responses to damage-associated molecular patterns (DAMPs) are involved in hypertension. However, the mechanisms of this contribution are not well understood. Circulating mitochondrial DNA is a DAMP that activates Toll-like receptor (TLR) 9 and is elevated in spontaneously hypertensive rats (SHR). Therefore, we hypothesized that lysosomotropic agent chloroquine (CQ) would impair TLR9 signaling, as well as prevent the development of hypertension and immune cell recruitment to the vasculature, in SHR...
September 13, 2016: American Journal of Hypertension
Meng Zhou, Zhifa Wen, Feng Cheng, Jie Ma, Weixia Li, Hongyan Ren, Yemeng Sheng, Huixia Dong, Liwei Lu, Hong-Ming Hu, Li-Xin Wang
Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses in IL-10-depedent manner both in vitro and in vivo...
July 2016: Oncoimmunology
Felipe V Pereira, Amanda C L Melo, Filipe M de Melo, Diego Mourão-Sá, Priscila Silva, Rodrigo Berzaghi, Carolina C A Herbozo, Jordana Coelho-Dos-Reis, Jorge A Scutti, Clarice S T Origassa, Rosana M Pereira, Luis Juliano, Maria Aparecida Juliano, Adriana K Carmona, Niels O S Câmara, Moriya Tsuji, Luiz R Travassos, Elaine G Rodrigues
Despite the recent approval of new agents for metastatic melanoma, its treatment remains challenging. Moreover, few available immunotherapies induce a strong cellular immune response, and selection of the correct immunoadjuvant is crucial for overcoming this obstacle. Here, we studied the immunomodulatory properties of arazyme, a bacterial metalloprotease, which was previously shown to control metastasis in a murine melanoma B16F10-Nex2 model. The antitumor activity of arazyme was independent of its proteolytic activity, since heat-inactivated protease showed comparable properties to the active enzyme; however, the effect was dependent on an intact immune system, as antitumor properties were lost in immunodeficient mice...
July 2016: Oncoimmunology
Ningwen Tai, Jian Peng, Fuqiang Liu, Elke Gulden, Youjia Hu, Xiaojun Zhang, Li Chen, F Susan Wong, Li Wen
Both animal model and human studies indicate that commensal bacteria may modify type 1 diabetes (T1D) development. However, the underlying mechanisms by which gut microbes could trigger or protect from diabetes are not fully understood, especially the interaction of commensal bacteria with pathogenic CD8 T cells. In this study, using islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8 T cell receptor NY8.3 transgenic nonobese diabetic mice, we demonstrated that MyD88 strongly modulates CD8(+) T cell-mediated T1D development via the gut microbiota...
September 19, 2016: Journal of Experimental Medicine
Yohei Takeda, Masahiro Azuma, Misako Matsumoto, Tsukasa Seya
BACKGROUND: Dendritic cells (DCs) mount tumor-associated antigens (TAAs), and the double-stranded RNA adjuvant Poly(I:C) stimulates Toll-like receptor 3 (TLR3) signal in DC, which in turn induces type I interferon (IFN) and interleukin-12 (IL-12), then cross-primes cytotoxic T lymphocytes (CTLs). Proliferation of CTLs correlates with tumor regression. How these potent cells expand with high quality is crucial to the outcome of CTL therapy. However, good markers reflecting the efficacy of DC-target immunotherapy have not been addressed...
2016: Journal of Experimental & Clinical Cancer Research: CR
Linh Pham Van, Nathalie Germaud, Abdulraouf Ramadan, Nathalie Thieblemont
The contribution of dysregulated innate immune responses to the pathogenesis of allergic disease remains largely unknown. Herein, we addressed the role of Toll-like receptor signaling in airway inflammation by studying mice rendered deficient for the myeloid differentiation factor 88 (MyD88(-/-)) which results in concurrent deficiencies in TLR and IL-1R1 signaling pathways. We show that the lack of MyD88 offers a partial protection from allergic disease evidenced by reduced airway eosinophilia and production of the Th17-associated effector cytokine IL-17A...
August 26, 2016: Cellular Immunology
Chao Li, Li-Min Zhang, Xue Zhang, Xia Huang, Yong Liu, Ming-Qiang Li, Shuai Xing, Tao Yang, Lin Xie, Feng-Chao Jiang, Han-Ying Jiang, Wen-Tao He, Ping Zhou
BACKGROUND: Most strategies for anti-rejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models...
September 8, 2016: Transplantation
Rafiou Agoro, Julie Piotet-Morin, Jennifer Palomo, Chloé Michaudel, Solenne Vigne, Isabelle Maillet, Pauline Chenuet, Noëlline Guillou, Jessica Le Bérichel, Malgorzata Kisielow, Ulf Per Flodby, Marc Le Bert, Valérie Quesniaux, Matthias Muller, Franco Di Padova, Bernhard Ryffel, Cem Gabay, Aurélie Couturier-Maillard
Allergic asthma is characterized by a strong Th2 response with inflammatory cell recruitment and structural changes in the lung. Papain is a protease allergen disrupting the airway epithelium triggering a rapid inflammation with eosinophilia mediated by innate lymphoid cell activation (ILC2) and leading to a Th2 immune response. In this study, we focused on inflammatory responses to a single exposure to papain and showed that intranasal administration of papain results in the recruitment of inflammatory cells, including neutrophils and eosinophils with a rapid production of IL-1α, IL-1β, and IL-33...
August 28, 2016: European Journal of Immunology
Huafeng Wang, Mengyi Li, Chiung Yu Hung, Meenal Sinha, Linda M Lee, Darin L Wiesner, Vanessa LeBert, Tassanee Lerksuthirat, Kevin Galles, Marulasiddappa Suresh, Anthony L DeFranco, Clifford A Lowell, Bruce S Klein, Marcel Wüthrich
Soaring rates of systemic fungal infections worldwide underscore the need for vaccine prevention. An understanding of the elements that promote vaccine immunity is essential. We previously reported that Th17 cells are required for vaccine immunity to the systemic dimorphic fungi of North America, and that Card9 and MyD88 signaling are required for the development of protective Th17 cells. Herein, we investigated where, when and how MyD88 regulates T cell development. We uncovered a novel mechanism in which MyD88 extrinsically regulates the survival of activated T cells during the contraction phase and in the absence of inflammation, but is dispensable for the expansion and differentiation of the cells...
August 2016: PLoS Pathogens
Wenjun Li, Hsi-Min Hsiao, Ryuji Higashikubo, Brian T Saunders, Ankit Bharat, Daniel R Goldstein, Alexander S Krupnick, Andrew E Gelman, Kory J Lavine, Daniel Kreisel
It is well established that maladaptive innate immune responses to sterile tissue injury represent a fundamental mechanism of disease pathogenesis. In the context of cardiac ischemia reperfusion injury, neutrophils enter inflamed heart tissue, where they play an important role in potentiating tissue damage and contributing to contractile dysfunction. The precise mechanisms that govern how neutrophils are recruited to and enter the injured heart are incompletely understood. Using a model of cardiac transplant-mediated ischemia reperfusion injury and intravital 2-photon imaging of beating mouse hearts, we determined that tissue-resident CCR2(+) monocyte-derived macrophages are essential mediators of neutrophil recruitment into ischemic myocardial tissue...
August 4, 2016: JCI Insight
F C Mansilla, M E Quintana, N P Cardoso, A V Capozzo
We demonstrated recently that immunization with recombinant Neospora caninum profilin (rNcPRO) induces limited protection and a regulatory T-cell response in mice. The aim of this study was to evaluate the immune response elicited by rNcPRO in cattle and assess a strategy to enhance its immunogenicity, combining the addition of T-cell epitopes and immune modulators. We developed a chimeric recombinant profilin fused to functional T-cell epitopes present in the N-terminal sequence of vesicular stomatitis virus (VSV) glycoprotein G (rNcPRO/G)...
August 11, 2016: Parasite Immunology
Xue Zhang, Shuai Xing, Mingqiang Li, Limin Zhang, Lin Xie, Wentao He, Jianhua Liu, Sheng Chang, Fengchao Jiang, Ping Zhou
INTRODUCTION AND AIMS: Studies have reported that myeloid differentiation factor 88 (MyD88) plays an important role in the development of type 1 diabetes (T1D). The aim of this study was to determine the effects of the self-created MyD88 inhibitor, TJ-M2010-6, in preventing and treating T1D. METHODS: Molecule docking and co-immunoprecipitation were used to determine the suppressing capability of TJ-M2010-6 on the homodimerization of MyD88. The preventive and therapeutic effects of TJ-M2010-6 were tested in NOD mice...
September 2016: Metabolism: Clinical and Experimental
Vishal Singh, Beng San Yeoh, Benoit Chassaing, Benyue Zhang, Piu Saha, Xia Xiao, Deepika Awasthi, Rangaiah Shashidharamurthy, Madhu Dikshit, Andrew Gewirtz, Matam Vijay-Kumar
BACKGROUND & AIMS: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. METHODS: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration...
July 2016: Cellular and Molecular Gastroenterology and Hepatology
Carl-Fredrik Johnzon, Elin Rönnberg, Bengt Guss, Gunnar Pejler
Mast cells have been shown to express vascular endothelial growth factor (VEGF), thereby implicating mast cells in pro-angiogenic processes. However, the mechanism of VEGF induction in mast cells and the possible expression of VEGF in fully mature mast cells have not been extensively studied. Here, we report that terminally differentiated peritoneal cell-derived mast cells can be induced to express VEGF in response to challenge with Staphylococcus aureus, thus identifying a mast cell-bacteria axis as a novel mechanism leading to VEGF release...
2016: Frontiers in Immunology
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