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Laëtitia Le Texier, Katie E Lineburg, Benjamin Cao, Cameron McDonald-Hyman, Lucie Leveque-El Mouttie, Jemma Nicholls, Michelle Melino, Blessy C Nalkurthi, Kylie A Alexander, Bianca Teal, Stephen J Blake, Fernando Souza-Fonseca-Guimaraes, Christian R Engwerda, Rachel D Kuns, Steven W Lane, Michele Teng, Charis Teh, Daniel Gray, Andrew D Clouston, Susan K Nilsson, Bruce R Blazar, Geoffrey R Hill, Kelli P A MacDonald
Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (Atg) in association with enhanced survival of Tregs after SCT. Autophagy is a self-degradative process for cytosolic components that promotes cell homeostasis and survival...
September 22, 2016: JCI Insight
Anna Malgorzata White, David C Wraith
The immune system evolved to respond to foreign invaders and prevent autoimmunity to self-antigens. Several types of regulatory T cells facilitate the latter process. These include a subset of Foxp3(-) CD4(+) T cells able to secrete IL-10 in an antigen-specific manner, type 1 regulatory (Tr1) T cells. Although their suppressive function has been confirmed both in vitro and in vivo, their phenotype remains poorly defined. It has been suggested that the surface markers LAG-3 and CD49b are biomarkers for murine and human Tr1 cells...
2016: Frontiers in Immunology
Matthew J Butcher, Adam R Filipowicz, Tayab C Waseem, Christopher McGary, Kevin J Crow, Nathaniel Magilnick, Mark Boldin, Patric S Lundberg, Elena Galkina
RATIONALE: Foxp3(+)T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. OBJECTIVE: Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe(-/-) mice, and what effect Treg plasticity might have on the pathology of atherosclerosis...
September 15, 2016: Circulation Research
Ana Villegas-Mendez, Colette A Inkson, Tovah N Shaw, Patrick Strangward, Kevin N Couper
CD4(+) T cells that produce IFN-γ are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp. The fate of these CD4(+)IFN-γ(+)IL-10(+) T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown. In this study, utilizing IFN-γ-yellow fluorescent protein (YFP) and IL-10-GFP dual reporter mice, we show that primary malaria infection-induced CD4(+)YFP(+)GFP(+) T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4(+) T cell memory population during the maintenance phase postinfection...
September 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yun-Peng Peng, Chun-Hua Xi, Yi Zhu, Ling-Di Yin, Ji-Shu Wei, Jing-Jing Zhang, Xin-Chun Liu, Song Guo, Yue Fu, Yi Miao
The progression of pancreatic cancer (PC) is significantly associated with tumor immune escape, which may be associated with nature killer (NK) cell dysfunction. CD226, CD96, and TIGIT, which share the ligand CD155, play important roles in the regulation of NK cell function. The present study was conducted to investigate the roles of these molecules in NK cells from PC patients. Expression of these molecules on NK cells was detected from samples of 92 pancreatic cancer patients and 40 healthy controls. The expression of CD155 was also evaluated by immunohistochemistry in 88 pancreatic cancer tissues...
September 10, 2016: Oncotarget
Stephen J Blake, William C Dougall, John J Miles, Michele W L Teng, Mark J Smyth
The receptors CD96 and TIGIT are expressed on the surface of T and natural killer (NK) cells, and recent studies suggest both play important inhibitory roles in immune function. CD96 has been shown to modulate immune cell activity in mice, with Cd96(-)(/)(-) mice displaying hypersensitive NK-cell responses to immune challenge and significant tumor resistance. TIGIT overexpression has been shown to reduce NK-cell-mediated cytotoxicity. TIGIT is also upregulated on T cells during cancer and chronic viral infection, with expression associated with effector T-cell exhaustion and increased regulatory T-cell suppression...
September 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Neha Jariwala, Bernice Benoit, Andrew V Kossenkov, Landon K Oetjen, Timothy M Whelan, Christine M Cornejo, Junko Takeshita, Brian S Kim, Louise C Showe, Maria Wysocka, Alain H Rook
No abstract text is available yet for this article.
September 1, 2016: Journal of Investigative Dermatology
Xie Jinhua, Wang Ji, Cheng Shouliang, Zheng Liangfeng, Ji Feiyue, Yang Lin, Zhang Yan, Ji Haoming
Inhibition of immune checkpoint proteins (checkpoints) has become a promising anti-esophageal cancer strategy. We here tested expressions of immune checkpoints in human esophageal cancers. Our results showed the expressions of many immune checkpoints, including CD28, CD27, CD137L, programmed death 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3), T cell Ig and ITIM domain (TIGIT), CD160, cytotoxic T lymphocyte antigen 4 (CTLA-4), CD200, CD137 and CD158, were dysregulated in peripheral T cells of esophageal cancer patients...
August 25, 2016: Oncotarget
B Hervé, D Fauvert, R Dard, J Roume, S Cognard, D Goidin, F Lozach, D Molina-Gomes, F Vialard
Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. It was recently reported that a microdeletion at the 3q13.31 locus is associated with a new syndrome combining developmental delay, postnatal overgrowth and dysmorphic features. However, the reciprocal microduplication has only been described in a few case reports displaying some clinical features of the microdeletion syndrome. Here, we report on a female infant with a 3.34 Mb microduplication of the 3q13...
September 2016: European Journal of Medical Genetics
Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R Spellman, Sarah Cooley, Michael R Verneris, Bruce R Blazar, Jeffrey S Miller
Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome...
October 1, 2016: Cancer Research
Tihana Lenac Rovis, Paola Kucan Brlic, Noa Kaynan, Vanda Juranic Lisnic, Ilija Brizic, Stefan Jordan, Adriana Tomic, Daria Kvestak, Marina Babic, Pinchas Tsukerman, Marco Colonna, Ulrich Koszinowski, Martin Messerle, Ofer Mandelboim, Astrid Krmpotic, Stipan Jonjic
The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation...
August 22, 2016: Journal of Experimental Medicine
Rémi Fromentin, Wendy Bakeman, Mariam B Lawani, Gabriela Khoury, Wendy Hartogensis, Sandrina DaFonseca, Marisela Killian, Lorrie Epling, Rebecca Hoh, Elizabeth Sinclair, Frederick M Hecht, Peter Bacchetti, Steven G Deeks, Sharon R Lewin, Rafick-Pierre Sékaly, Nicolas Chomont
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals...
July 2016: PLoS Pathogens
Lin Zhang, Jian Wang, Feng Wei, Kaiyuan Wang, Qian Sun, Fan Yang, Hao Jin, Yu Zheng, Hua Zhao, Limei Wang, Wenwen Yu, Xiying Zhang, Yang An, Lili Yang, Xinwei Zhang, Xiubao Ren
Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM- 3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture...
June 7, 2016: Oncotarget
Anna E Vilgelm, Douglas B Johnson, Ann Richmond
Immune-checkpoint blockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune-checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune-checkpoint inhibitors with other anti-cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen...
August 2016: Journal of Leukocyte Biology
Ana C Anderson, Nicole Joller, Vijay K Kuchroo
Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity...
May 17, 2016: Immunity
Yosuke Kano, Takahiro Iguchi, Hiroto Matsui, Keishi Adachi, Yukimi Sakoda, Tomoya Miyakawa, Shun Doi, Shoichi Hazama, Hiroaki Nagano, Yoshiya Ueyama, Koji Tamada
Therapeutic cancer vaccines are designed to treat cancer by boosting the endogenous immune system to fight against the cancer. In the development of clinically effective cancer vaccines, one of the most practical objectives is to identify adjuvants that are capable of optimizing the vaccine effects. In this study, we explored the potential of polyinosinic-polycytidylic acid (poly(I:C)) and LAG-3-Ig (soluble recombinant protein of lymphocyte activation gene-3 [LAG-3] extracellular domain fused with human IgG Fc region) as adjuvants for P1A tumor antigen peptide vaccine in a pre-established P815 mouse tumor model with a transfer of tumor-specific T cells...
April 2016: Cancer Science
Matthieu Collin
INTRODUCTION: Immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies, are revolutionizing therapeutic concepts in the treatment of cancer. Said class of drugs will represent a multi-billion dollar market over the coming decade. Many companies have therefore developed important patent activities in the field. AREAS COVERED: The present review gives an overview of the patent literature during the period 2010-2015 in the field of immune checkpoint inhibitors...
May 2016: Expert Opinion on Therapeutic Patents
Evangelia Kourepini, Nikolaos Paschalidis, Davina C M Simoes, Maria Aggelakopoulou, Jane L Grogan, Vily Panoutsakopoulou
T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed that Tigit expression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Isabelle Serr, Rainer W Fürst, Peter Achenbach, Martin G Scherm, Füsun Gökmen, Florian Haupt, Eva-Maria Sedlmeier, Annette Knopff, Leonard Shultz, Richard A Willis, Anette-Gabriele Ziegler, Carolin Daniel
Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo...
2016: Nature Communications
Hao Wu, Yuxin Chen, Hong Liu, Lin-Lin Xu, Paula Teuscher, Shixia Wang, Shan Lu, Alexander L Dent
Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However, Tfr-cell function in the GC is not well understood. Here, we define Tfr cells as a CD4(+) Foxp3(+) CXCR5(hi) PD-1(hi) CD25(low) TIGIT(high) T-cell population. Furthermore, we have used a novel mouse model ("Bcl6FC") to delete the Bcl6 gene in Foxp3(+) T cells and thus specifically deplete Tfr cells...
May 2016: European Journal of Immunology
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