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https://www.readbyqxmd.com/read/29906526/promidis%C3%AE-a-tcr%C3%AE-signature-associated-with-immunodeficiencies-caused-by-v-d-j-recombination-defects
#1
Aurélie Berland, Jérémie Rosain, Sophie Kaltenbach, Vincent Allain, Nizar Mahlaoui, Isabelle Melki, Alice Fievet, Catherine Dubois d'Enghien, Marie Ouachée-Chardin, Laurence Perrin, Nathalie Auger, Funda Erol Cipe, Andrea Finocchi, Figen Dogu, Felipe Suarez, Despina Moshous, Thierry Leblanc, Alexandre Belot, Claire Fieschi, David Boutboul, Marion Malphettes, Lionel Galicier, Eric Oksenhendler, Stéphane Blanche, Alain Fischer, Patrick Revy, Dominique Stoppa-Lyonnet, Capucine Picard, Jean-Pierre de Villartay
- BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), its suboptimal activity, is associated with a broad spectrum of immune manifestations such as late onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, in particular when it involves myelo-ablative conditioning regimen for hematopoietic stem cell transplantation (HSCT)...
June 12, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29895573/the-mutation-associated-neoantigen-functional-expansion-of-specific-t-cells-manafest-assay-a-sensitive-platform-for-monitoring-antitumor-immunity
#2
Ludmila Danilova, Valsamo Anagnostou, Justina X Caushi, John-William Sidhom, Haidan Guo, Hok Yee Chan, Prerna Suri, Ada J Tam, Jiajia Zhang, Margueritta El Asmar, Kristen A Marrone, Jarushka Naidoo, Julie R Brahmer, Patrick M Forde, Alexander S Baras, Leslie Cope, Victor E Velculescu, Drew Pardoll, Franck Housseau, Kellie N Smith
Mutation-associated neoantigens (MANAs) are a target of antitumor T-cell immunity. Sensitive, simple, and standardized assays are needed to assess the repertoire of functional MANA-specific T cells in oncology. Assays analyzing in vitro cytokine production such as ELISpot and intracellular cytokine staining (ICS) have been useful but have limited sensitivity in assessing tumor-specific T-cell responses and do not analyze antigen-specific T-cell repertoires. The FEST (Functional Expansion of Specific T cells) assay described herein integrates TCR sequencing of short-term, peptide-stimulated cultures with a bioinformatic platform to identify antigen-specific clonotypic amplifications...
June 12, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29891556/in-rheumatoid-arthritis-synovitis-at-different-inflammatory-sites-is-dominated-by-shared-but-patient-specific-t-cell-clones
#3
Anne Musters, Paul L Klarenbeek, Marieke E Doorenspleet, Giulia Balzaretti, Rebecca E E Esveldt, Barbera D C van Schaik, Aldo Jongejan, Sander W Tas, Antoine H C van Kampen, Frank Baas, Niek de Vries
Genetic and immunological evidence clearly points to a role for T cells in the pathogenesis of rheumatoid arthritis (RA). Selective targeting of such disease-associated T cell clones might be highly effective while having few side effects. However, such selective targeting may only be feasible if the same T cell clones dominate the immune response at different sites of inflammation. We leveraged high-throughput technology to quantitatively assess whether different T cell clones dominate the inflammatory infiltrate at various sites of inflammation in this prototypic autoimmune disease...
June 11, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29889140/genetic-and-nongenetic-factors-that-may-predispose-individuals-to-allergic-drug-reactions
#4
Andrew Gibson, Monday Ogese, Munir Pirmohamed
PURPOSE OF REVIEW: Defining predisposition to allergic drug reactions has largely focussed on HLA associations, but other genetic and nongenetic factors are also likely to be involved. RECENT FINDINGS: Polymorphic genetic variants in cytokine genes, including IL-10, and co-signalling pathways, including CTLA4, have been associated with allergic drug reactions, but the effect size is lower than with HLA alleles and most associations have not been replicated. Although TCR specificity seems to be important for CBZ-induced SJS/TEN in South East Asian patients, a distinct repertoire may not play a role in reactions to other drugs...
June 7, 2018: Current Opinion in Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29884700/deep-sequencing-reveals-transient-segregation-of-t-cell-repertoires-in-splenic-t-cell-zones-during-an-immune-response
#5
Johannes Textor, Anke Fähnrich, Martin Meinhardt, Cornelia Tune, Sebastian Klein, Rene Pagel, Peter König, Kathrin Kalies, Jürgen Westermann
Immunological differences between hosts, such as diverse TCR repertoires, are widely credited for reducing the risk of pathogen spread and adaptation in a population. Within-host immunological diversity might likewise be important for robust pathogen control, but to what extent naive TCR repertoires differ across different locations in the same host is unclear. T cell zones (TCZs) in secondary lymphoid organs provide secluded microenvironmental niches. By harboring distinct TCRs, such niches could enhance within-host immunological diversity...
June 8, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29868003/repseq-data-representativeness-and-robustness-assessment-by-shannon-entropy
#6
Wahiba Chaara, Ariadna Gonzalez-Tort, Laura-Maria Florez, David Klatzmann, Encarnita Mariotti-Ferrandiz, Adrien Six
High-throughput sequencing (HTS) has the potential to decipher the diversity of T cell repertoires and their dynamics during immune responses. Applied to T cell subsets such as T effector and T regulatory cells, it should help identify novel biomarkers of diseases. However, given the extreme diversity of TCR repertoires, understanding how the sequencing conditions, including cell numbers, biological and technical sampling and sequencing depth, impact the experimental outcome is critical to proper use of these data...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29867987/cd154-costimulation-shifts-the-local-t-cell-receptor-repertoire-not-only-during-thymic-selection-but-also-during-peripheral-t-dependent-humoral-immune-responses
#7
Anke Fähnrich, Sebastian Klein, Arnauld Sergé, Christin Nyhoegen, Sabrina Kombrink, Steffen Möller, Karsten Keller, Jürgen Westermann, Kathrin Kalies
CD154 is a transmembrane cytokine expressed transiently on activated CD4 T cells upon T-cell receptor (TCR) stimulation that interacts with CD40 on antigen-presenting cells. The signaling via CD154:CD40 is essential for B-cell maturation and germinal center formation and also for the final differentiation of CD4 T cells during T-dependent humoral immune responses. Recent data demonstrate that CD154 is critically involved in the selection of T-cell clones during the negative selection process in the thymus. Whether CD154 signaling influences the TCR repertoire during peripheral T-dependent humoral immune responses has not yet been elucidated...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29867961/human-%C3%AE-%C3%AE-t-cells-from-surface-receptors-to-the-therapy-of-high-risk-leukemias
#8
REVIEW
Vito Pistoia, Nicola Tumino, Paola Vacca, Irene Veneziani, Alessandro Moretta, Franco Locatelli, Lorenzo Moretta
γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1). γδ T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for Vγ9Vδ2 TCR), MICA-B and UL16 binding protein (for NKG2D), and PVR and Nectin-2 (for DNAM-1). They also respond to cytokines undergoing proliferation and release of cytokines/chemokines...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29790966/tcrmodel-high-resolution-modeling-of-t-cell-receptors-from-sequence
#9
Ragul Gowthaman, Brian G Pierce
T cell receptors (TCRs), along with antibodies, are responsible for specific antigen recognition in the adaptive immune response, and millions of unique TCRs are estimated to be present in each individual. Understanding the structural basis of TCR targeting has implications in vaccine design, autoimmunity, as well as T cell therapies for cancer. Given advances in deep sequencing leading to immune repertoire-level TCR sequence data, fast and accurate modeling methods are needed to elucidate shared and unique 3D structural features of these molecules which lead to their antigen targeting and cross-reactivity...
May 22, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29789755/regulatory-mechanisms-in-t-cell-receptor-signalling
#10
REVIEW
Guillaume Gaud, Renaud Lesourne, Paul E Love
The remarkable T cell receptor (TCR) performs essential functions in the initiation of intracellular signals required for T cell development, repertoire selection and effector responses to foreign antigens. How TCR signals elicit such diverse cellular responses and outcomes remains a major question for investigation. Recent years have witnessed important advances in our understanding of the regulatory processes that control and modulate the TCR signalling response. Here, we review newly identified mechanisms for the regulation of TCR signalling and then discuss how the TCR signalling response is regulated to control two critical cellular processes - namely, positive selection and T cell homeostasis...
May 22, 2018: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/29789121/aire-is-not-essential-for-regulating-neuroinflammatory-disease-in-mice-transgenic-for-human-autoimmune-diseases-associated-mhc-class-ii-genes-hla-dr2b-and-hla-dr4
#11
Saisha A Nalawade, Niannian Ji, Itay Raphael, Andrew Pratt, Ellen Kraig, Thomas G Forsthuber
The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire-/- ) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates...
May 14, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29784760/formation-of-the-intrathymic-dendritic-cell-pool-requires-ccl21-mediated-recruitment-of-ccr7-progenitors-to-the-thymus
#12
Emilie J Cosway, Izumi Ohigashi, Karin Schauble, Sonia M Parnell, William E Jenkinson, Sanjiv Luther, Yousuke Takahama, Graham Anderson
During αβ T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2...
May 21, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29776088/how-nonuniform-contact-profiles-of-t-cell-receptors-modulate-thymic-selection-outcomes
#13
Hanrong Chen, Arup K Chakraborty, Mehran Kardar
T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies...
March 2018: Physical Review. E
https://www.readbyqxmd.com/read/29765548/transformation-of-mouse-t-cells-requires-myc-and-akt-activity-in-conjunction-with-inhibition-of-intrinsic-apoptosis
#14
Kari Högstrand, Stephanie Darmanin, TachaZi Plym Forshell, Alf Grandien
Peripheral T-cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by excessive proliferation of transformed mature T cells. The number and nature of genetic aberrations required and sufficient for transformation of normal T cells into lymphomas is unknown. Here, using a combinatorial in vitro -approach, we demonstrate that overexpression of MYC together with activated AKT in conditions of inhibition of intrinsic apoptosis rapidly resulted in transformation of mature mouse T cells with a frequency approaching 100%...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29757191/disease-driving-cd4-t-cell-clonotypes-persist-for-decades-in-celiac-disease
#15
Louise F Risnes, Asbjørn Christophersen, Shiva Dahal-Koirala, Ralf S Neumann, Geir K Sandve, Vikas K Sarna, Knut Ea Lundin, Shuo-Wang Qiao, Ludvig M Sollid
Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer-sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined...
May 14, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29752423/strong-homeostatic-tcr-signals-induce-formation-of-self-tolerant-virtual-memory-cd8-t-cells
#16
Ales Drobek, Alena Moudra, Daniel Mueller, Martina Huranova, Veronika Horkova, Michaela Pribikova, Robert Ivanek, Susanne Oberle, Dietmar Zehn, Kathy D McCoy, Peter Draber, Ondrej Stepanek
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells...
May 11, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29752065/cd36-mediates-cell-surface-antigens-to-promote-thymic-development-of-the-regulatory-t-cell-receptor-repertoire-and-allo-tolerance
#17
Justin S A Perry, Emilie V Russler-Germain, You W Zhou, Whitney Purtha, Matthew L Cooper, Jaebok Choi, Mark A Schroeder, Vanessa Salazar, Takeshi Egawa, Byeong-Chel Lee, Nada A Abumrad, Brian S Kim, Mark S Anderson, John F DiPersio, Chyi-Song Hsieh
The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens...
April 30, 2018: Immunity
https://www.readbyqxmd.com/read/29735644/invariant-nkt-cells-and-control-of-the-thymus-medulla
#18
REVIEW
Andrea J White, Beth Lucas, William E Jenkinson, Graham Anderson
Most αβ T cells that form in the thymus are generated during mainstream conventional thymocyte development and involve the generation and selection of a diverse αβ TCR repertoire that recognizes self-peptide/MHC complexes. Additionally, the thymus also supports the production of T cell subsets that express αβ TCRs but display unique developmental and functional features distinct from conventional αβ T cells. These include multiple lineages of CD1d-restricted invariant NKT (iNKT) cells that express an invariant αβ TCR, branch off from mainstream thymocytes at the CD4+ CD8+ stage, and are potent producers of polarizing cytokines...
May 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29731752/resetting-the-t-cell-compartment-in-autoimmune-diseases-with-autologous-hematopoietic-stem-cell-transplantation-an-update
#19
REVIEW
Lisanne Lutter, Julia Spierings, Femke C C van Rhijn-Brouwer, Jacob M van Laar, Femke van Wijk
Autologous hematopoietic stem cell transplantation (aHSCT) for autoimmune diseases has been applied for two decades as a treatment for refractory patients with progressive disease. The rationale behind aHSCT is that high-dose immunosuppression eliminates autoreactive T and B cells, thereby resetting the immune system. Post-aHSCT the cytotoxic CD8+ T cells normalize via clonal expansion due to homeostatic proliferation within a few months. CD4+ T cells recover primarily via thymopoiesis resulting in complete renewal of the T cell receptor (TCR) repertoire which requires years or never normalize completely...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29721371/complimentary-mechanisms-of-dual-checkpoint-blockade-expand-unique-t-cell-repertoires-and-activate-adaptive-anti-tumor-immunity-in-triple-negative-breast-tumors
#20
Erika J Crosby, Junping Wei, Xiao Yi Yang, Gangjun Lei, Tao Wang, Cong-Xiao Liu, Pankaj Agarwal, Alan J Korman, Michael A Morse, Kenneth Gouin, Simon R V Knott, H Kim Lyerly, Zachary C Hartman
Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB...
2018: Oncoimmunology
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