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https://www.readbyqxmd.com/read/28103947/long-term-immune-reconstitution-and-t-cell-repertoire-analysis-after-autologous-hematopoietic-stem-cell-transplantation-in-systemic-sclerosis-patients
#1
Dominique Farge, Lucas C M Arruda, Fanny Brigant, Emmanuel Clave, Corinne Douay, Zora Marjanovic, Christophe Deligny, Guitta Maki, Eliane Gluckman, Antoine Toubert, Helene Moins-Teisserenc
The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6 years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n = 5) or non-responders (B, n = 5), using modified Rodnan's skin score (mRSS) and forced vital capacity (FVC%)...
January 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28093446/tumor-infiltrating-merkel-cell-polyomavirus-specific-t-cells-are-diverse-and-associated-with-improved-patient-survival
#2
Natalie J Miller, Candice D Church, Lichun Dong, David Crispin, Matthew P Fitzgibbon, Kristina Lachance, Lichen Jing, Michi Shinohara, Ioannis Gavvovidis, Gerald Willimsky, Martin McIntosh, Thomas Blankenstein, David M Koelle, Paul Nghiem
Tumor-infiltrating CD8(+) T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8(+) T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, "KLL") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer(+) CD8(+) T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry...
January 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28077600/ibrutinib-therapy-increases-t-cell-repertoire-diversity-in-patients-with-chronic-lymphocytic-leukemia
#3
Qingsong Yin, Mariela Sivina, Harlan Robins, Erik Yusko, Marissa Vignali, Susan O'Brien, Michael J Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G Wierda, Jan A Burger
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy...
January 11, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28074285/t-cell-receptor-repertoire-usage-in-cancer-as-a-surrogate-marker-for-immune-responses
#4
REVIEW
David Schrama, Cathrin Ritter, Jürgen C Becker
Characterizing the interaction of cancer cells with the host adaptive immune system is critical for understanding tumor immunology and the modus operandi of immunotherapeutic interventions to treat cancer. As the key cellular effectors of adaptive immunity, T cells are endowed with specialized receptors (the T cell receptor; TCR), to recognize and to eliminate cancer cells. The diversity of the TCR repertoire results from specialized genetic diversification mechanisms that generate an incredible variability allowing recognizing extensive collections of antigens...
January 10, 2017: Seminars in Immunopathology
https://www.readbyqxmd.com/read/28072859/increased-pd-1-expression-and-altered-t-cell-repertoire-diversity-predict-mortality-in-patients-with-septic-shock-a-preliminary-study
#5
Atsutoshi Tomino, Masanobu Tsuda, Ruri Aoki, Yuka Kajita, Masamitsu Hashiba, Tsuguaki Terajima, Hideki Kano, Naoshi Takeyama
Sepsis causes impairment of innate and adaptive immunity by multiple mechanisms, including depletion of immune effector cells and T cell exhaustion. Although lymphocyte dysfunction is associated with increased mortality and potential reactivation of latent viral infection in patients with septic shock, the relation between viral reactivation and lymphocyte dysfunction is obscure. The objectives of this study were 1) to determine the relation of lymphocyte dysfunction to viral reactivation and mortality, and 2) to evaluate recovery of lymphocyte function during septic shock, including T cell receptor (TCR) diversity and the expression of programmed death 1 (PD-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28062695/the-clonal-invariant-nkt-cell-repertoire-in-people-with-type-1-diabetes-is-characterized-by-a-loss-of-clones-expressing-high-affinity-tcrs
#6
Anna S Tocheva, Salah Mansour, Tristan G H Holt, Samuel Jones, Andrew Chancellor, Joseph P Sanderson, Efrem Eren, Tim J Elliott, Richard I G Holt, Stephan D Gadola
Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production...
January 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28039161/the-different-t-cell-receptor-repertoires-in-breast-cancer-tumors-draining-lymph-nodes-and-adjacent-tissues
#7
Ting Wang, Changxi Wang, Jinghua Wu, Chenyang He, Wei Zhang, Jiayun Liu, Ruifang Zhang, Yonggang Lv, Yongping Li, Xiaojing Zeng, Hongzhi Cao, Xiuqing Zhang, Xun Xu, Chen Huang, Ling Wang, Xiao Liu
T lymphocytes infiltrate the microenvironment of breast cancer (BC) tumors and play a pivotal role in tumor immune surveillance. Relationships between the T-cell receptors (TCRs) borne by T cells within tumors, in the surrounding tissues, and in draining lymph nodes are largely unexplored in human breast cancer. Consequently, information about the relative extent of possible T-cell exchange between these tissues is also lacking. Here we have analyzed the TCR repertoire of T cells using multiplex PCR and high throughput sequencing of the TCRβ chain in the tissues of tumor, adjacent nontumor, and axillary lymph-nodes of breast cancer patients...
December 30, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/28026094/phenotypic-characteristics-of-aged-cd4-cd28-null-t-lymphocytes-are-determined-by-changes-in-the-whole-genome-dna-methylation-pattern
#8
Beatriz Suarez-Álvarez, Ramón M Rodríguez, Karin Schlangen, Aroa Baragaño Raneros, Leonardo Márquez-Kisinousky, Agustín F Fernández, Carmen Díaz-Corte, Ana M Aransay, Carlos López-Larrea
Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4(+) lymphocytes (CD28(null) T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28(null) T cells and its CD28(+) counterpart...
December 27, 2016: Aging Cell
https://www.readbyqxmd.com/read/28018351/allorecognition-of-hla-c-mismatches-by-cd8-t-cells-in-hematopoietic-stem-cell-transplantation-is-a-complex-interplay-between-mismatched-peptide-binding-region-residues-hla-c-expression-and-hla-dpb1-disparities
#9
Florence Bettens, Stéphane Buhler, Jean-Marie Tiercy
HLA-C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C MMs, we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56(-)CD137(+)CD8(+) lymphocytes in HLA-C incompatible combinations...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28012713/accurate-quantification-of-t-cells-by-measuring-loss-of-germline-t-cell-receptor-loci-with-generic-single-duplex-droplet-digital-pcr-assays
#10
Willem H Zoutman, Rogier J Nell, Mieke Versluis, Debby van Steenderen, Rajshri N Lalai, Jacoba J Out-Luiting, Mark J de Lange, Maarten H Vermeer, Anton W Langerak, Pieter A van der Velden
Quantifying T cells accurately in a variety of tissues of benign, inflammatory, or malignant origin can be of great importance in a variety of clinical applications. Flow cytometry and immunohistochemistry are considered to be gold-standard methods for T-cell quantification. However, these methods require fresh, frozen, or fixated cells and tissue of a certain quality. In addition, conventional and droplet digital PCR (ddPCR), whether followed by deep sequencing techniques, have been used to elucidate T-cell content by focusing on rearranged T-cell receptor (TCR) genes...
December 21, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28009290/inhibition-of-ror%C3%AE-t-skews-tcr%C3%AE-gene-rearrangement-and-limits-t-cell-repertoire-diversity
#11
Yanxia Guo, Kenzie D MacIsaac, Yi Chen, Richard J Miller, Renu Jain, Barbara Joyce-Shaikh, Heidi Ferguson, I-Ming Wang, Razvan Cristescu, John Mudgett, Laura Engstrom, Kyle J Piers, Gretchen A Baltus, Kenneth Barr, Hongjun Zhang, Huseyin Mehmet, Laxminarayan G Hegde, Xiao Hu, Laura L Carter, Thomas D Aicher, Gary Glick, Dennis Zaller, Abbas Hawwari, Craig C Correll, Dallas C Jones, Daniel J Cua
Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4(+)CD8(+) (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28003262/defining-the-clonality-of-peripheral-t-cell-lymphomas-using-rna-seq
#12
Scott D Brown, Greg Hapgood, Christian Steidl, Andrew P Weng, Kerry J Savage, Robert A Holt
MOTIVATION: In T-cell lymphoma, malignant T cells arising from a founding clone share an identical T cell receptor (TCR) and can be identified by the over-representation of this TCR relative to TCRs from the patient's repertoire of normal T cells. Here, we demonstrate that TCR information extracted from RNA-seq data can provide a higher resolution view of peripheral T cell lymphomas (PTCLs) than that provided by conventional methods. RESULTS: For 60 subjects with PTCL, flow cytometry/FACS was used to identify and sort aberrant T cell populations from diagnostic lymph node cell suspensions...
December 21, 2016: Bioinformatics
https://www.readbyqxmd.com/read/27976744/low-affinity-cd4-t-cells-are-major-responders-in-the-primary-immune-response
#13
Ryan J Martinez, Rakieb Andargachew, Hunter A Martinez, Brian D Evavold
A robust primary immune response has been correlated with the precursor number of antigen-specific T cells, as identified using peptide MHCII tetramers. However, these tetramers identify only the highest-affinity T cells. Here we show the entire CD4+ T-cell repertoire, inclusive of low-affinity T cells missed by tetramers, using a T-cell receptor (TCR) signalling reporter and micropipette assay to quantify naive precursors and expanded populations. In vivo limiting dilution assays reveal hundreds more precursor T cells than previously thought, with higher-affinity tetramer-positive T cells, comprising only 5-30% of the total antigen-specific naive repertoire...
December 15, 2016: Nature Communications
https://www.readbyqxmd.com/read/27942583/tissue-distribution-and-clonal-diversity-of-the-t-and-b-cell-repertoire-in-type-1-diabetes
#14
Howard R Seay, Erik Yusko, Stephanie J Rothweiler, Lin Zhang, Amanda L Posgai, Martha Campbell-Thompson, Marissa Vignali, Ryan O Emerson, John S Kaddis, Dave Ko, Maki Nakayama, Mia J Smith, John C Cambier, Alberto Pugliese, Mark A Atkinson, Harlan S Robins, Todd M Brusko
The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), "irrelevant" nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects (n = 18) and control donors (n = 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4(+) conventional T cells (Tconv), CD4(+) Treg, CD8(+) T cells, and B cells...
December 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27941777/gvl-effects-in-t-prolymphocytic-leukemia-evidence-from-mrd-kinetics-and-tcr-repertoire-analyses
#15
L Sellner, M Brüggemann, M Schlitt, H Knecht, D Herrmann, T Reigl, A Krejci, V Bystry, N Darzentas, M Rieger, S Dietrich, T Luft, A D Ho, M Kneba, P Dreger
Allogeneic stem cell transplantation (alloSCT) is used for treating patients with T-prolymphocytic leukemia (T-PLL). However, direct evidence of GvL activity in T-PLL is lacking. We correlated minimal residual disease (MRD) kinetics with immune interventions and T-cell receptor (TCR) repertoire diversity alterations in patients after alloSCT for T-PLL. Longitudinal quantitative MRD monitoring was performed by clone-specific real-time PCR of TCR rearrangements (n=7), and TCR repertoire diversity assessment by next-generation sequencing (NGS; n=3) Although post-transplant immunomodulation (immunosuppression tapering or donor lymphocyte infusions) resulted in significant reduction (>1 log) of MRD levels in 7 of 10 occasions, durable MRD clearance was observed in only two patients...
December 12, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27933066/functionally-diverse-nk-like-t-cells-are-effectors-and-predictors-of-successful-aging
#16
REVIEW
Joshua J Michel, Patricia Griffin, Abbe N Vallejo
The fundamental challenge of aging and long-term survivorship is maintenance of functional independence and compression of morbidity despite a life history of disease. Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27899444/antigen-dependent-competition-shapes-the-local-repertoire-of-tissue-resident-memory-cd8-t-cells
#17
Andreas Muschaweckh, Veit R Buchholz, Anne Fellenzer, Christian Hessel, Paul-Albert König, Sha Tao, Ronny Tao, Mathias Heikenwälder, Dirk H Busch, Thomas Korn, Wolfgang Kastenmüller, Ingo Drexler, Georg Gasteiger
Tissue-resident memory CD8(+) T cells (TRM) constitute a major component of the immune-surveillance system in nonlymphoid organs. Local, noncognate factors are both necessary and sufficient to support the programming of TRM cell fate in tissue-infiltrating T cells. Recent evidence suggests that TCR signals received in infected nonlymphoid tissues additionally contribute to TRM cell formation. Here, we asked how antigen-dependent pathways influence the generation of skin-resident memory T cells that arise from a polyclonal repertoire of cells induced by infection with an antigenically complex virus and recombinant vaccine vector...
December 12, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27894837/cd4-virtual-memory-antigen-inexperienced-t-cells-reside-in-the-na%C3%A3-ve-regulatory-and-memory-t-cell-compartments-at-similar-frequencies-implications-for-autoimmunity
#18
Alina I Marusina, Yoko Ono, Alexander A Merleev, Michiko Shimoda, Hiromi Ogawa, Elizabeth A Wang, Kayo Kondo, Laura Olney, Guillaume Luxardi, Yoshinori Miyamura, Tilahun D Yilma, Itzel Bustos Villalobos, Jennifer W Bergstrom, Daniel G Kronenberg, Athena M Soulika, Iannis E Adamopoulos, Emanual Maverakis
It is widely accepted that central and effector memory CD4(+) T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts...
November 25, 2016: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27881740/peripheral-self-reactivity-regulates-antigen-specific-cd8-t-cell-responses-and-cell-division-under-physiological-conditions
#19
Lee Kim Swee, Zhen Wei Tan, Anna Sanecka, Nagisa Yoshida, Harshil Patel, Gijsbert Grotenbreg, Eva-Maria Frickel, Hidde L Ploegh
T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity-hence reactivity to self-and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2(b) haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L(d)-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels...
November 2016: Open Biology
https://www.readbyqxmd.com/read/27880974/deep-sequencing-of-the-tcrb-repertoire-of-human-foxp3-and-foxp3-t-cells-suggests-that-they-are-completely-distinct-and-non-overlapping
#20
Amit Golding, Samuel Darko, William H Wylie, Daniel C Douek, Ethan M Shevach
Maintenance of peripheral tolerance requires a balance between auto-reactive conventional T cells (Tconv) and thymically-derived Foxp3(+) regulatory T cells (tTregs). Considerable controversy exists regarding the similarities/differences in TCR repertoires expressed by Tconv and tTregs. We generated highly purified populations of human adult and cord blood Tconv and tTregs based on the differential expression of CD25 and CD127. The purity of the sorted populations was validated by intracellular staining for Foxp3 and Helios...
November 23, 2016: Clinical and Experimental Immunology
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