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t cell anergy

Isabel Mérida, Pedro Torres-Ayuso, Antonia Ávila-Flores, Javier Arranz-Nicolás, Elena Andrada, María Tello-Lafoz, Rosa Liébana, Raquel Arcos
Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the activation of the PLCγ/Ras/ERK axis, providing a critical checkpoint to inhibit T cell responses. Upregulation of these isoforms limits Ras activation, leading to hypo-responsive, anergic states similar to those caused by tumors. Recent studies have identified DGKα upregulation in tumor lymphocyte infiltrates, and cells from DGKα and ζ deficient mice show enhanced antitumor activity, suggesting that limitation of DAG based signals by DGK is used by tumors to evade immune attack...
September 23, 2016: Advances in Biological Regulation
Dublu Lal Gupta, Sanjeev Bhoi, Teena Mohan, Sagar Galwnkar, D N Rao
INTRODUCTION: Multiple organ dysfunction syndrome (MODS) developed due to the insult of trauma is a leading cause of death. The high mortality rate in these patients with and without sepsis has been reported up to 50%, throughout the world and thus required an urgent insight to overcome this problem. OBJECTIVE: The aim of this study is to examine the differential changes in subsets of T cells, imbalance in cytokine profile, immune-paralysis (T cell anergy) in Trauma hemorrhagic shock (THS) and post traumatic sepsis patients...
December 2016: Cytokine
Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Séverine Ciré, Sylvie Da Rocha, Maxime Ferrand, Mary K Collins, Anne Galy
Lymph node stromal cells play a role in self-tolerance by presenting tissue antigens to T cells. Yet, immunomodulatory properties of lymphoid tissue stroma, particularly toward CD4+ T cells, remain insufficiently characterized by lack of tools to target antigens for presentation by stromal cells. A lentiviral vector was therefore designed for antigen delivery to MHC class II(+) cells of nonhematopoietic origin. Following intravenous vector delivery, the transgene was detected in lymph node gp38+ stromal cells which were CD45- MHCII+ and partly positive for CD86 and CTLA4 or B7-H4...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Shizuka Ohtsuka, Shuhei Ogawa, Ei Wakamatsu, Ryo Abe
Suppression of T cell growth is an important mechanism for establishment of self-tolerance and prevention of unwanted prolonged immune responses that may cause tissue damage. Although negative selection of potentially self-reactive T cells in the thymus as well as in peripheral tissues has been extensively investigated and well-documented, regulatory mechanisms to dampen proliferation of antigen-specific effector T cells in response to antigen stimulation remain largely unknown. Thus, in this work we focus on the identification of growth suppression mechanisms of antigen-specific effector T cells...
August 19, 2016: International Immunology
Charlotte R Grant, Rodrigo Liberal
There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets...
August 12, 2016: Clinics and Research in Hepatology and Gastroenterology
Dürdal Us
Superantigens (SAgs) are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism. They cause polyclonal activation of T cells in a non-specific manner, by binding to a particular variable-beta (Vβ) chain of T-cell receptor (TCR) and MHC class II molecule, in unprocessed form and outside of peptide-binding cleft, forming a bridge between the antigen presenting cell and the T cell. SAgs are classified into three groups, namely 1) exogenous (soluble proteins and exotoxins secreted by microorganisms), 2) endogenous (transmembrane proteins encoded by viruses which are integrated into the genome) and 3) B-cell SAgs (proteins which stimulate predominantly B cells)...
July 2016: Mikrobiyoloji Bülteni
Paulina García-González, Gabriela Ubilla-Olguín, Diego Catalán, Katina Schinnerling, Juan Carlos Aguillón
Dendritic cells (DCs) control immune responses by driving potent inflammatory actions against external and internal threats while generating tolerance to self and harmless components. This duality and their potential to reprogram immune responses in an antigen-specific fashion have made them an interesting target for immunotherapeutic strategies to control autoimmune diseases. Several protocols have been described for in vitro generation of tolerogenic DCs (tolDCs) capable of modulating adaptive immune responses and restoring tolerance through different mechanisms that involve anergy, generation of regulatory lymphocyte populations, or deletion of potentially harmful inflammatory T cell subsets...
July 30, 2016: Autoimmunity Reviews
William L Redmond, Stefanie N Linch
Numerous preclinical studies have demonstrated that combination immunotherapy can significantly reduce tumor growth and improve overall survival as compared to monotherapy. Furthermore, dual CTLA-4/PD-1 checkpoint blockade recently received FDA-approval for patients with metastatic melanoma, becoming the first combination immunotherapy to garner this designation in a rapidly evolving field. Despite this progress, the majority of patients do not respond to treatment, underscoring the critical need for more effective therapies...
July 26, 2016: Human Vaccines & Immunotherapeutics
Nicholas M Provine, Rafael A Larocca, Malika Aid, Pablo Penaloza-MacMaster, Alexander Badamchi-Zadeh, Erica N Borducchi, Kathleen B Yates, Peter Abbink, Marinela Kirilova, David Ng'ang'a, Jonathan Bramson, W Nicholas Haining, Dan H Barouch
CD4(+) T cell help is critical for optimal CD8(+) T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8(+) T cell responses in the absence of CD4(+) T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4(+) T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8(+) T cell functionality and differentiation. Unhelped CD8(+) T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Damiano M Rovituso, Laura Scheffler, Marie Wunsch, Christoph Kleinschnitz, Sebastian Dörck, Jochen Ulzheimer, Antonios Bayas, Lawrence Steinman, Süleyman Ergün, Stefanie Kuerten
B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1(+) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84...
July 20, 2016: Scientific Reports
Andreas Kupz, Ulrike Zedler, Manuela Stäber, Stefan H E Kaufmann
Infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death in human immunodeficiency virus (HIV)+ individuals, particularly in Sub-Saharan Africa. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection. Here we describe a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals...
2016: PloS One
Luuk van Hooren, Maria Georganaki, Hua Huang, Sara M Mangsbo, Anna Dimberg
CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma...
July 1, 2016: Oncotarget
Mónica Pascual-García, Cristina Bértolo, Juan C Nieto, Neus Serrat, Íñigo Espinosa, Emanuela D'Angelo, Raquel Muñoz, Ramón Rovira, Silvia Vidal, Jaime Prat
Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti-tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group...
October 2016: Human Pathology
Javier Merayo-Chalico, Sandra Rajme-López, Ana Barrera-Vargas, Jorge Alcocer-Varela, Mariana Díaz-Zamudio, Diana Gómez-Martín
Lymphopenia is strongly associated with autoimmune diseases. The molecular mechanisms that link both phenomena are still unclear, but certain key pathways have been described. Central tolerance is as important as peripheral. In the earlier, epithelial and dendritic cells play a crucial role in the selection of clones. In the latter, regulatory T cells (Tregs) rise as inductors of anergy in order to prevent the development of autoimmune pathology. In lymphopenic conditions, T cells develop the process of lymphopenia-induced proliferation (LIP)...
October 2016: Human Immunology
Fernando Concha-Benavente, Raghvendra Srivastava, Soldano Ferrone, Robert L Ferris
Experimental as well as clinical studies demonstrate that the immune system plays a major role in controlling generation and progression of tumors. The cancer immunoediting theory supports the notion that tumor cell immunogenicity is dynamically shaped by the immune system, as it eliminates immunogenic tumor cells in the early stage of the disease and then edits their antigenicity. The end result is the generation of a tumor cell population able to escape from immune recognition and elimination by tumor infiltrating lymphocytes...
July 2016: Oral Oncology
Rong Wang, Aizhang Xu, Xueying Zhang, Jie Wu, Andrew Freywald, Jianqing Xu, Jim Xiang
CD8(+) cytotoxic T lymphocyte (CTL) exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin (OVA)-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 (PD-1) and lymphocyte-activation gene-3 (LAG-3) and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-γ production and cytolytic effects...
June 6, 2016: Cellular & Molecular Immunology
Andrew W Woodham, Lisa Yan, Joseph G Skeate, Daniel van der Veen, Heike H Brand, Michael K Wong, Diane M Da Silva, W Martin Kast
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs...
December 2016: Papillomavirus Research
Travis J Friesen, Qingyong Ji, Pamela J Fink
T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen...
May 30, 2016: Journal of Experimental Medicine
Ehsan Malek, Marcos de Lima, John J Letterio, Byung-Gyu Kim, James H Finke, James J Driscoll, Sergio A Giralt
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress innate and adaptive immune responses that promote tumor growth. MDSCs are increased in patients with multiple myeloma (MM) and have bidirectional interaction with tumors within the MM microenvironment. MM-MDSCs promote MM tumor growth and induce immune suppression; conversely, MM cells induce MDSC development and survival. Although the role of MDSCs in infections, inflammatory diseases and solid tumors has been extensively characterized, their tumor-promoting and immune-suppressive role in MM and the MM microenvironment is only beginning to emerge...
September 2016: Blood Reviews
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