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https://www.readbyqxmd.com/read/28525897/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#1
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515320/recognition-of-nectin-2-by-the-natural-killer-cell-receptor-tigit
#2
Felix A Deuss, Benjamin S Gully, Jamie Rossjohn, Richard Berry
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. While the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μM, which was moderately lower than the affinity observed for the TIGIT-necl-5 interaction (3...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28472085/transcriptomic-immunologic-signature-associated-with-favorable-clinical-outcome-in-basal-like-breast-tumors
#3
Sandra Martínez-Canales, Francisco Cifuentes, Miguel López De Rodas Gregorio, Leticia Serrano-Oviedo, Eva María Galán-Moya, Eitan Amir, Atanasio Pandiella, Balázs Győrffy, Alberto Ocaña
BACKGROUND: Most patients with early stage triple negative breast cancer (TNBC) receive adjuvant chemotherapy. Activation of the immune system is associated with tumor response and may help identify TNBC with favorable outcome. METHODS: Gene expression data were obtained from the GEO Dataset GDS2250/GSE3744. Affymetrix CEL files were downloaded and analyzed with Affymetrix Transcriptome Analysis Console 3.0. Functional genomics was implemented with David Bioinformatics Resources 6...
2017: PloS One
https://www.readbyqxmd.com/read/28438433/contribution-of-inhibitory-receptor-tigit-to-nk-cell-education
#4
Yuke He, Hui Peng, Rui Sun, Haiming Wei, Hans-Gustaf Ljunggren, Wayne M Yokoyama, Zhigang Tian
Engagement of inhibitory receptors by cognate host MHC-I molecules triggers NK cell education, resulting in functional maturation and allowing NK cells to sense missing-self. However, NK cells also express inhibitory receptors for non-MHC-I ligands and their role in NK cell education is poorly understood. TIGIT is a recently identified inhibitory receptor that recognizes a non-MHC-I ligand CD155. Here, we demonstrated that TIGIT(+) NK cells from wild-type mice exerted augmented responsiveness to various stimuli, including targets that lacked expression of CD155 ligand...
April 21, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28374110/htlv-1-infection-and-neuropathogenesis-in-the-context-of-rag1-%C3%AE-c-rag1-hu-and-blt-mice
#5
Rashida Ginwala, Breanna Caruso, Zafar K Khan, Ajinkya Pattekar, Glen M Chew, Michael J Corley, Ronak Loonawat, Steven Jacobson, Sreesha Sreedhar, Lishomwa C Ndhlovu, Pooja Jain
To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1(-/-)γc(-/-) or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34(+) hematopoietic stem cells...
April 4, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28335609/early-and-delayed-antiretroviral-therapy-results-in-comparable-reductions-in-cd8-t-cell-exhaustion-marker-expression
#6
Rachel Lena Rutishauser, Wendy Hartogensis, Christian Deo Deguit, Melissa Krone, Rebecca Hoh, Frederick M Hecht, Christopher D Pilcher, Peter Bacchetti, Steven G Deeks, Peter W Hunt, Joseph M McCune
In untreated HIV infection, CD8(+) T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8(+) T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction...
April 25, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28325871/progression-of-type-1-diabetes-from-the-prediabetic-stage-is-controlled-by-interferon-%C3%AE-signaling
#7
Brett S Marro, Brian C Ware, Jaroslav Zak, Juan Carlos de la Torre, Hugh Rosen, Michael B A Oldstone
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28290453/suppressive-il-17a-foxp3-and-ex-th17-il-17a-neg-foxp3-treg-cells-are-a-source-of-tumour-associated-treg-cells
#8
Stephanie Downs-Canner, Sara Berkey, Greg M Delgoffe, Robert P Edwards, Tyler Curiel, Kunle Odunsi, David L Bartlett, Nataša Obermajer
Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3(+) cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A(+)Foxp3(+) and ex-Th17 Foxp3(+) cells are converted from IL-17A(+)Foxp3(neg) cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A(+), ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets...
March 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28284938/human-il-6r-hi-tigit-cd4-cd127-low-cd25-t-cells-display-potent-in-vitro-suppressive-capacity-and-a-distinct-th17-profile
#9
Ricardo C Ferreira, Daniel B Rainbow, Arcadio Rubio García, Marcin L Pekalski, Linsey Porter, João J Oliveira, Frank Waldron-Lynch, Linda S Wicker, John A Todd
To date many clinical studies aim to increase the number and/or fitness of CD4(+)CD127(low)CD25(+) regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4(+)CD127(low)CD25(+) TIGIT(-) T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6R(hi)TIGIT(+) Tregs...
March 9, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28282368/elevated-expression-of-immunoreceptor-tyrosine-based-inhibitory-motif-tigit-on-t-lymphocytes-is-correlated-with-disease-activity-in-rheumatoid-arthritis
#10
Qing Luo, Zhen Deng, Chuxin Xu, Lulu Zeng, Jianqing Ye, Xue Li, Yang Guo, Zikun Huang, Junming Li
BACKGROUND It is well known that lymphocytes play an important role in rheumatoid arthritis (RA). T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (TIGIT) have immunosuppressive co-stimulatory molecules that mediate inhibitory effects, but their roles in RA are poorly understood. MATERIAL AND METHODS Were recruited 76 patients with RA and 33 healthy controls (HC). Clinical manifestations, laboratory measurements, physical examination, and medical history of RA patients were recorded...
March 10, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28261278/elevated-expression-of-tigit-on-cd3-cd4-t-cells-correlates-with-disease-activity-in-systemic-lupus-erythematosus
#11
Qing Luo, Jianqing Ye, Lulu Zeng, Xue Li, Le Fang, Beihua Ju, Zikun Huang, Junming Li
OBJECTIVES: It is well-known that lymphocytes play an important role in systemic lupus erythematosus (SLE). T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT) is one of immunosuppressive costimulatory molecules that mediates an inhibitory effect. However, its roles in SLE are poorly understood. This study was designed to investigate the correlation between the frequencies of TIGIT-expressing CD3(+)CD4(+) T lymphocytes and SLE. METHODS: Patients with SLE were recruited from the First Affiliated Hospital of Nanchang University...
2017: Allergy, Asthma, and Clinical Immunology
https://www.readbyqxmd.com/read/28258695/tigit-and-cd96-new-checkpoint-receptor-targets-for-cancer-immunotherapy
#12
REVIEW
William C Dougall, Sema Kurtulus, Mark J Smyth, Ana C Anderson
While therapies targeting the co-inhibitory or immune checkpoint receptors PD-1 and CTLA-4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co-stimulatory receptor CD226 form a pathway that is analogous to the CD28/CTLA-4 pathway, in which shared ligands and differential receptor:ligand affinities fine-tune the immune response...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28236750/targeting-nk-cell-checkpoints-for-cancer-immunotherapy
#13
REVIEW
Aura Muntasell, Maria C Ochoa, Luna Cordeiro, Pedro Berraondo, Ascension López-Díaz de Cerio, Mariona Cabo, Miguel López-Botet, Ignacio Melero
Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity. Recombinant cytokines (i.e., IL-15 and IL-2), antibodies blocking inhibitory receptors (i.e., KIR, NKG2A and TIGIT) and agonists delivering signals via CD137, NKG2D and CD16 stand out as the most suitable opportunities...
February 22, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28138156/antibody-dependent-cell-cytotoxicity-immunotherapy-strategies-enhancing-effector-nk-cells
#14
REVIEW
Maria Carmen Ochoa, Luna Minute, Inmaculada Rodriguez, Saray Garasa, Elisabeth Perez-Ruiz, Susana Inogés, Ignacio Melero, Pedro Berraondo
Antibody-dependent cellular cytotoxicity (ADCC) is a set of mechanisms that target cells coated with IgG antibodies of the proper subclasses (IgG1 in the human) to be the prey of cell-to-cell cytolysis executed by immune cells expressing FcRIIIA (CD16A). These effectors include not only natural killer (NK) cells but also other CD16(+) subsets such as monocyte/macrophages, NKT cells or γδ T cells. In cancer therapy, ADCC is exploited by antibodies that selectively recognize proteins on the surface of malignant cells...
April 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28125551/o-003-the-brain-as-extraintestinal-ibd-manifestation-are-brain-and-cognitive-differences-in-pediatric-crohn-s-disease-associated-with-immune-gene-expression
#15
Christine Mrakotsky, Dunn W Augustine, Christopher Watson, James Canavan, Michael Rivkin, Scott Snapper
BACKGROUND: Structural brain changes in gray and white matter have been previously found in adults with Crohn's disease (CD). We have recently shown similar effects for pediatric CD in 2 separate studies (Mrakotsky et al., 2012, 2013, 2015), particularly for cortical and subcortical brain regions important for cognition, memory and emotion. Our prior data also revealed serum markers of inflammation and steroid therapy to be negatively associated with cortical thickness, subcortical volume, cognitive and school function, however, associations between brain structure and more detailed inflammatory profiles have not been studied...
February 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28108989/tigit-signalling-pathway-negatively-regulates-cd4-t-cell-responses-in-systemic-lupus-erythematosus
#16
Lie Mao, Hongyan Hou, Shiji Wu, Yu Zhou, Juan Wang, Jing Yu, Xiaohui Wu, Yanfang Lu, Liyan Mao, Munyemana Jean Bosco, Feng Wang, Ziyong Sun
B-lymphocyte hyperactivity in systemic lupus erythematosus (SLE) is T-cell-dependent, and CD4(+) T-cell activation is essential to SLE pathogenesis. However, the mechanism of the deregulation of CD4(+) T cells in SLE is largely unknown. T-cell immunoglobulin and ITIM domain (TIGIT) is a new inhibitory receptor preferentially expressed on activated CD4(+) T cells. Here, we address the role of TIGIT in the pathogenesis of SLE. Our results showed that TIGIT expression on CD4(+) T cells was significantly elevated in patients with SLE and highly correlated with the activity of the disease...
January 20, 2017: Immunology
https://www.readbyqxmd.com/read/28046066/htlv-1-bzip-factor-enhances-t-cell-proliferation-by-impeding-the-suppressive-signaling-of-co-inhibitory-receptors
#17
Haruka Kinosada, Jun-Ichirou Yasunaga, Kazuya Shimura, Paola Miyazato, Chiho Onishi, Tomonori Iyoda, Kayo Inaba, Masao Matsuoka
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28035916/the-paired-receptors-tigit-and-dnam-1-as-targets-for-therapeutic-antibodies
#18
Natan Stein, Pinchas Tsukerman, Ofer Mandelboim
One of the most exciting fields in modern medicine is immunotherapy, treatment which looks to harness the power of the immune system to fight disease. A particularly effective strategy uses antibodies designed to influence the activity levels of the immune system. Here we look at two receptors - TIGIT and DNAM-1 - which bind the same ligands but have opposite effects on immune cells, earning them the label `paired receptors'. Importantly, natural killer cells and cytotoxic T cells express both of these receptors, and in certain cases their effector functions are dictated by TIGIT or DNAM-1 signaling...
2017: Human Antibodies
https://www.readbyqxmd.com/read/27979840/early-effector-t-lymphocytes-coexpress-multiple-inhibitory-receptors-in-primary-non-small-cell-lung-cancer
#19
Elena Tassi, Giulia Grazia, Claudia Vegetti, Ilaria Bersani, Giulia Bertolini, Alessandra Molla, Paola Baldassari, Francesca Andriani, Luca Roz, Gabriella Sozzi, Ugo Pastorino, Roberta Mortarini, Andrea Anichini
Clinical efficacy of PD-1/PD-L1 targeting relies upon the reactivation of tumor-specific but functionally impaired PD-1(+) T cells present before therapy. Thus, analyzing early-stage primary tumors may reveal the presence of T cells that are not yet functionally impaired. In this study, we report that activated (HLA-DR(+)) T cells with an effector memory (TEM) profile are enriched in such lesions. Tumor-infiltrating lymphocytes coexpressed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3, and TIGIT, but also displayed a recently activated, nonexhausted phenotype...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/27978489/structural-mutational-and-biophysical-studies-reveal-a-canonical-mode-of-molecular-recognition-between-immune-receptor-tigit-and-nectin-2
#20
Dibyendu Samanta, Haisu Guo, Rotem Rubinstein, Udupi A Ramagopal, Steven C Almo
In addition to antigen-specific stimulation of T cell receptor (TCR) by a peptide-MHC complex, the functional outcome of TCR engagement is regulated by antigen-independent costimulatory signals. Costimulatory signals are provided by an array of interactions involving activating and inhibitory receptors expressed on T cells and their cognate ligands on antigen presenting cells. T cell immunoglobulin and ITIM domain (TIGIT), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or poliovirus receptor (PVR), inhibits activation of T and NK cells...
January 2017: Molecular Immunology
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