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tcr repertoire

Hiroyuki Inoue, Jae-Hyun Park, Kazuma Kiyotani, Makda Zewde, Azusa Miyashita, Masatoshi Jinnin, Yukiko Kiniwa, Ryuhei Okuyama, Ryota Tanaka, Yasuhiro Fujisawa, Hiroshi Kato, Akimichi Morita, Jun Asai, Norito Katoh, Kenji Yokota, Masashi Akiyama, Hironobu Ihn, Satoshi Fukushima, Yusuke Nakamura
Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment...
2016: Oncoimmunology
Lorenza Rattazzi, Giuseppa Piras, Samuel Brod, Koval Smith, Masahiro Ono, Fulvio D'Acquisto
T cells are known to be plastic and to change their phenotype according to the cellular and biochemical milieu they are embedded in. In this study, we transposed this concept at a macroscopic level assessing whether changes in the environmental housing conditions of C57/BL6 mice would influence the phenotype and function of T cells. Our study shows that exposure to 2 weeks in an enriched environment (EE) does not impact the T cell repertoire in vivo and causes no changes in the early TCR-driven activation events of these cells...
2016: Frontiers in Immunology
Xiaofang Cao, Qingbiao Wa, Qidi Wang, Lin Li, Xin Liu, Lisha An, Ruikun Cai, Meng Du, Yue Qiu, Jian Han, Chunlin Wang, Xingyu Wang, Changlong Guo, Yonghong Lu, Xu Ma
Psoriasis is a T cell-mediated chronic inflammatory skin disease with inflammatory cell infiltrates in the dermis and epidermis. Previous studies suggested that there are some expanded T-cell receptor (TCR) clones in psoriatic skin. However, the effect of psoriasis on the immunological characteristics of TCR in circulating blood has not been reported. To address this, we performed high-throughput sequencing to reveal the immunological characteristics of TCR beta chain (TRB) in both psoriasis patients and healthy controls...
October 12, 2016: International Immunopharmacology
Dane M Newman, Anne K Voss, Tim Thomas, Rhys S Allan
Histone acetylation has an important role in gene regulation, DNA replication, and repair. Because these processes are central to the development of the immune system, we investigated the role of a previously unstudied histone acetyltransferase named KAT7 (also known as Myst2 or HBO1) in the regulation of thymopoiesis and observed a critical role in the regulation of conventional and innate-like T cell development. We found that KAT7-deficient thymocytes displayed normal, positive selection and development into mature single-positive αβ thymocytes; however, we observed few peripheral CD4(+) or CD8(+) T cells...
October 12, 2016: Journal of Leukocyte Biology
Kazutaka Kitaura, Tadasu Shini, Takaji Matsutani, Ryuji Suzuki
BACKGROUND: High-throughput sequencing of T cell receptor (TCR) genes is a powerful tool for analyses of antigen specificity, clonality and diversity of T lymphocytes. Here, we developed a new TCR repertoire analysis method using 454 DNA sequencing technology in combination with an adaptor-ligation mediated polymerase chain reaction (PCR). This method allows the amplification of all TCR genes without PCR bias. To compare gene usage, diversity and similarity of expressed TCR repertoires among individuals, we conducted next-generation sequencing (NGS) of TRA and TRB genes in peripheral blood mononuclear cells from 20 healthy human individuals...
October 11, 2016: BMC Immunology
Stephanie Gras, Jesseka Chadderton, Claudia M Del Campo, Carine Farenc, Florian Wiede, Tracy M Josephs, Xavier Y X Sng, Michiko Mirams, Katherine A Watson, Tony Tiganis, Kylie M Quinn, Jamie Rossjohn, Nicole L La Gruta
The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8(+) T cell response to an H-2D(b)-restricted nucleoprotein epitope (NP366) is characterized by preferential expansion of T cells bearing TRBV13(+) T cell receptors (TCRs) and avoidance of TRBV17(+) T cells, despite the latter dominating the naive precursor repertoire. We found two TRBV17(+) TCRs that bound H-2D(b)-NP366 with a 180° reversed polarity compared to the canonical TCR-pMHC-I docking...
September 24, 2016: Immunity
Nicholas R J Gascoigne, Vasily Rybakin, Oreste Acuto, Joanna Brzostek
Thymocyte selection involves the positive and negative selection of the repertoire of T cell receptors (TCRs) such that the organism does not suffer autoimmunity, yet has the benefit of the ability to recognize any invading pathogen. The signal transduced through the TCR is translated into a number of different signaling cascades that result in transcription factor activity in the nucleus and changes to the cytoskeleton and motility. Negative selection involves inducing apoptosis in thymocytes that express strongly self-reactive TCRs, whereas positive selection must induce survival and differentiation programs in cells that are more weakly self-reactive...
October 6, 2016: Annual Review of Cell and Developmental Biology
Dibyendu Kumar Das, Robert J Mallis, Jonathan S Duke-Cohan, Rebecca E Hussey, Paul W Tetteh, Mark Hilton, Gerhard Wagner, Matthew J Lang, Ellis Reinherz
The pre-T cell receptor (preTCR) is a pTα-β heterodimer functioning in early αβ T-cell development. Although once thought to be ligand-autonomous, recent studies show that preTCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe preTCR bonding with pMHC at the single molecule level. Like the αβTCR, the preTCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes, and exploiting allosteric control regulated via the Cβ FG loop region...
October 5, 2016: Journal of Biological Chemistry
Cara L Benjamin, Raymond P Stowe, Lisa St John, Clarence F Sams, Satish K Mehta, Brian E Crucian, Duane L Pierson, Krishna V Komanduri
Following the advent of molecular assays that measure T cell receptor excision circles (TRECs) present in recent thymic emigrants, it has been conclusively shown that thymopoiesis persists in most adults, but that functional output decreases with age, influencing the maintenance of a diverse and functional T cell receptor (TCR) repertoire. Space flight has been shown to result in a variety of phenotypic and functional changes in human T cells and in the reactivation of latent viruses. While space flight has been shown to influence thymic architecture in rodents, thymopoiesis has not previously been assessed in astronauts...
August 4, 2016: JCI Insight
Laura F Su, Daniel Del Alcazar, Erietta Stelekati, E John Wherry, Mark M Davis
The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide-MHC tetramers, we isolated rare specific Foxp3(+) cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
K A Pilones, R Emerson, S Formenti, S Demaria
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Benjamin D Solomon, Chyi-Song Hsieh
Foxp3(+)retinoic acid-related orphan receptor (ROR)γt(+) T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relationship to RORγt(-) regulatory T and Th17 cells remain unclear. In this study, we use a fixed TCRβ system to show that the TCR repertoire of the Foxp3(+)RORγt(+) population is mostly distinct compared with other colonic T cell subsets. However, of these TCRs, a fraction is also found in the Th17 subset, suggesting that TCR repertoire overlap may contribute to the reported ability of Foxp3(+)RORγt(+) cells to regulate Th17 immunity...
September 26, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Eri Ishikawa, Hidetaka Kosako, Tomoharu Yasuda, Masaki Ohmuraya, Kimi Araki, Tomohiro Kurosaki, Takashi Saito, Sho Yamasaki
Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected...
2016: Nature Communications
Colm Keane, Clare Gould, Kimberley Jones, David Hamm, Dipti Talaulikar, Jonathan Ellis, Frank Vari, Simone Birch, Erica Han, Peter Wood, Kim-Anh Le Cao, Michael R Green, Pauline Crooks, Sanjiv Jain, Joshua Tobin, Raymond J Steptoe, Maher K Gandhi
PURPOSE: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo Diffuse Large B-cell Lymphoma (DLBCL), and the TCR's impact on survival. EXPERIMENTAL DESIGN: We performed high-throughput unbiased TCRBeta sequencing on a population based cohort of 92 DLBCL patients treated with conventional (i.e. non-checkpoint blockade) frontline 'R-CHOP' therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString{trade mark, serif}...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Emma J Grant, Tracy M Josephs, Sophie A Valkenburg, Linda Wooldridge, Margaret Hellard, Jamie Rossjohn, Mandvi Bharadwaj, Katherine Kedzierska, Stephanie Gras
αβT cell receptor (TCR) genetic diversity is outnumbered by the quantity of pathogenic epitopes to be recognized. To provide efficient protective anti-viral immunity, a single TCR ideally needs to cross-react with a multitude of pathogenic epitopes. However, the frequency, extent, and mechanisms of TCR cross-reactivity remain unclear; with conflicting results on anti-viral T cell cross-reactivity observed in humans. Namely, both the presence and lack of T cell cross-reactivity has been reported with HLA-A*02:01-restricted epitopes from the Epstein-Barr and influenza viruses (BMLF-1 and M158, respectively) or with the hepatitis C and influenza viruses (NS31073 and NA231, respectively)...
September 19, 2016: Journal of Biological Chemistry
Rafael Di Marco Barros, Natalie A Roberts, Robin J Dart, Pierre Vantourout, Anett Jandke, Oliver Nussbaumer, Livija Deban, Sara Cipolat, Rosie Hart, Maria Luisa Iannitto, Adam Laing, Bradley Spencer-Dene, Philip East, Deena Gibbons, Peter M Irving, Pablo Pereira, Ulrich Steinhoff, Adrian Hayday
Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved...
September 22, 2016: Cell
Robert Root-Bernstein
I propose a T-cell receptor (TcR)-based mechanism by which immunity mediates both "genetic self" and "microbial self" thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross-reactivity with "self," resulting in selection for a TcR repertoire mimicking "genetic self." Second, evolution has selected for a "microbial self" that mimics "genetic self" so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it...
September 5, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Daniel Silberman, Sai Harsha Krovi, Kathryn D Tuttle, James Crooks, Richard Reisdorph, Janice White, James Gross, Jennifer L Matsuda, Laurent Gapin, Philippa Marrack, John W Kappler
The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
David B Page, Jianda Yuan, David Redmond, Y Hanna Wen, Jeremy C Durack, Ryan Emerson, Stephen Solomon, Zhiwan Dong, Phillip Wong, Christopher Comstock, Adi Diab, Janice Sung, Majid Maybody, Elizabeth Morris, Edi Brogi, Monica Morrow, Virgilio Sacchini, Olivier Elemento, Harlan Robins, Sujata Patil, James P Allison, Jedd D Wolchok, Clifford Hudis, Larry Norton, Heather L McArthur
In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab...
October 2016: Cancer Immunology Research
Aditi Sood, Mengqi Dong, Heather J Melichar
Thymic selection proceeds in a unique and highly organized thymic microenvironment resulting in the generation of a functional, self-tolerant T cell repertoire. In vitro models to study T lineage commitment and development have provided valuable insights into this process. However, these systems lack the complete three-dimensional thymic milieu necessary for T cell development and, therefore, are incomplete approximations of in vivo thymic selection. Some of the challenges related to modeling T cell development can be overcome by using in situ models that provide an intact thymic microenvironment that fully supports thymic selection of developing T cells...
2016: Journal of Visualized Experiments: JoVE
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