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https://www.readbyqxmd.com/read/28218745/human-%C3%AE-%C3%AE-t-cells-are-quickly-reconstituted-after-stem-cell-transplantation-and-show-adaptive-clonal-expansion-in-response-to-viral-infection
#1
Sarina Ravens, Christian Schultze-Florey, Solaiman Raha, Inga Sandrock, Melanie Drenker, Linda Oberdörfer, Annika Reinhardt, Inga Ravens, Maleen Beck, Robert Geffers, Constantin von Kaisenberg, Michael Heuser, Felicitas Thol, Arnold Ganser, Reinhold Förster, Christian Koenecke, Immo Prinz
To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private...
February 20, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28213366/tumor-infiltrating-and-peripheral-blood-t-cell-immunophenotypes-predict-early-relapse-in-localized-clear-cell-renal-cell-carcinoma
#2
Nicolas A Giraldo, Etienne Becht, Yann Vano, Florent Petitprez, Laetitia Lacroix, Pierre Validire, Rafael Sanchez-Salas, Alexandre Ingels, Stephane Marie Oudard, Audrey Moatti, Bénédicte Buttard, Sarah Bourras, Claire Germain, Xavier Cathelineau, Wolf-Herman Fridman, Catherine Sautes-Fridman
PURPOSE: The efficacy of PD-1 Checkpoint Blockade (ChB) as adjuvant therapy in localized clear cell Renal Cell Carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help to define which patients could benefit from ChB and to uncover new therapeutic targets. EXPERIMENTAL DESIGN: We performed multiparametric flow cytometry immunophenotypic analysis of T cells isolated from tumor tissue (TIL), adjacent non-malignant renal tissue (RIL) and peripheral blood (PBL), in a cohort of patients (n=40) with localized ccRCC...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28212502/a-new-mechanism-shapes-the-na%C3%A3-ve-cd8-t-cell-repertoire-the-selection-for-full-diversity
#3
Pedro Gonçalves, Marco Ferrarini, Carmen Molina-Paris, Grant Lythe, Florence Vasseur, Annik Lim, Benedita Rocha, Orly Azogui
During thymic T cell differentiation, TCR repertoires are shaped by negative, positive and agonist selection. In the thymus and in the periphery, repertoires are also shaped by strong inter-clonal and intra-clonal competition to survive death by neglect. Understanding the impact of these events on the T cell repertoire requires direct evaluation of TCR expression in peripheral naïve T cells. Several studies have evaluated TCR diversity, with contradictory results. Some of these studies had intrinsic technical limitations since they used material obtained from T cell pools, preventing the direct evaluation of clone sizes...
February 14, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28196891/insights-into-immune-system-development-and-function-from-mouse-t-cell-repertoires
#4
Zachary Sethna, Yuval Elhanati, Chrissy S Dudgeon, Curtis G Callan, Arnold J Levine, Thierry Mora, Aleksandra M Walczak
The ability of the adaptive immune system to respond to arbitrary pathogens stems from the broad diversity of immune cell surface receptors. This diversity originates in a stochastic DNA editing process (VDJ recombination) that acts on the surface receptor gene each time a new immune cell is created from a stem cell. By analyzing T-cell receptor (TCR) sequence repertoires taken from the blood and thymus of mice of different ages, we quantify the changes in the VDJ recombination process that occur from embryo to young adult...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28192476/th40-cells-cd4-cd40-tcells-drive-a-more-severe-form-of-experimental-autoimmune-encephalomyelitis-than-conventional-cd4-t-cells
#5
Gisela M Vaitaitis, Martin G Yussman, Dan M Waid, David H Wagner
CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). CD4 T cells expressing CD40 (Th40) are pathogenic in type I diabetes but have not been evaluated in EAE. We demonstrate here that Th40 cells drive a rapid, more severe EAE disease course than conventional CD4 T cells. Adoptively transferred Th40 cells are present in lesions in the CNS and are associated with wide spread demyelination...
2017: PloS One
https://www.readbyqxmd.com/read/28188172/t-cell-repertoires-in-refractory-coeliac-disease
#6
Julia Ritter, Karin Zimmermann, Korinna Jöhrens, Stefanie Mende, Anke Seegebarth, Britta Siegmund, Steffen Hennig, Kremena Todorova, Andreas Rosenwald, Severin Daum, Michael Hummel, Michael Schumann
OBJECTIVE: Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis...
February 10, 2017: Gut
https://www.readbyqxmd.com/read/28185879/ctla4-ig-effectively-controls-immune-activation-and-inflammatory-disease-in-a-novel-murine-model-of-leaky-scid
#7
Stéphanie Humblet-Baron, Susann Schönefeldt, Josselyn Garcia-Perez, Frédéric Baron, Emanuela Pasciuto, Adrian Liston
BACKGROUND: Severe combined immunodeficiency (SCID) can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as RAG1, RAG2 or DCLRE1C. Defective DNA recombination causes a developmental block in T cells and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give a partial loss of T cells, in a spectrum including leaky SCID (LS) and Omenn syndrome (OS). These patients not only develop life-threatening infections due to immunodeficiency, but also develop inflammatory/autoimmune conditions due to the presence of autoreactive T cells...
February 6, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28177966/high-number-of-activated-cd8-t-cells-targeting-hiv-antigens-are-present-in-cerebrospinal-fluid-in-acute-hiv-infection
#8
Cari F Kessing, Serena Spudich, Victor Valcour, Pearline Cartwright, Thep Chalermchai, James L K Fletcher, Carmen Nichols, Benjamin J Josey, Bonnie Slike, Shelly J Krebs, Napapon Sailsuta, Sukalaya Lerdlum, Linda Jagodzinski, Somporn Tipsuk, Duanghathai Suttichom, Somprartthana Rattanamanee, Henrik Zetterberg, Joanna Hellmuth, Nittaya Phanuphak, Merlin L Robb, Nelson L Michael, Jintanat Ananworanich, Lydie Trautmann
BACKGROUND: Central nervous system (CNS) infiltration by CD8+ T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8+ T cells in the CNS during acute HIV infection is unknown. METHODS: We analyzed the phenotype, gene expression, TCR repertoire and HIV-specificity of CD8+ T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of acute HIV infection (AHI) (n=26), chronic (n=23), and uninfected (n=8)...
February 7, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28177902/identification-of-patient-specific-and-tumor-shared-t-cell-receptor-sequences-in-renal-cell-carcinoma-patients
#9
Chiara Massa, Harlan Robins, Cindy Desmarais, Dagmar Riemann, Corinna Fahldieck, Paolo Fornara, Barbara Seliger
A major requirement for cancer immunotherapy is the development of biomarkers for prognosis and for monitoring therapy response. In an attempt to evaluate the immune response of renal cell carcinoma (RCC) patients, tumor lesions and / or blood samples from 12 RCC patients underwent deep T cell receptor (TCR) sequencing. Despite the low number of samples, different TCR distribution patterns could be detected. Most of the RCC patients presented "patient-specific" TCR sequences, and those clonotypes were present at higher frequency in tumor lesions suggesting a specific extravasation from the blood...
February 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28159798/destabilizing-the-autoinhibitory-conformation-of-zap70-induces-up-regulation-of-inhibitory-receptors-and-t-cell-unresponsiveness
#10
Lih-Yun Hsu, Debra A Cheng, Yiling Chen, Hong-Erh Liang, Arthur Weiss
Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII(+) thymocytes and in increased thymic and peripheral T regulatory cells...
February 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28159550/characterization-of-the-diversity-of-t-cell-receptor-%C3%AE-%C3%AE-complementary-determinant-region-3-in-human-peripheral-blood-by-immune-repertoire-sequencing
#11
Hui Chen, Mingjin Zou, Da Teng, Jianmin Zhang, Wei He
γδ T cells function as sentinels in early host response to infections and malignancies. Although γδ T cells are regarded as innate immune cells and recognize antigens in a non-MHC restricted manner, they possess a huge diversity of complementary determinant region 3 (CDR3) of T cell receptor (TCR) generated by the rearrangement of germ-line gene V- (D) -J-C fragments. However, the detailed characteristics of the TCRγδ CDR3 repertoire remain unclear. A comprehensive analysis would answer fundamental questions about the diversity of the TCRγδ CDR3 repertoire and elucidate the mechanism underlying γδ T cell recognition of pathogens and tumor antigens...
January 31, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28146579/selective-expansion-of-high-functional-avidity-memory-cd8-t-cell-clonotypes-during-hepatitis-c-virus-reinfection-and-clearance
#12
Mohamed S Abdel-Hakeem, Maude Boisvert, Julie Bruneau, Hugo Soudeyns, Naglaa H Shoukry
The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before, during and after hepatitis C virus (HCV) reinfection in patients who spontaneously resolved two consecutive infections (SR/SR) and patients who resolved a primary but failed to clear a subsequent infection (SR/CI)...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28141543/molecular-challenges-imposed-by-mhc-i-restricted-long-epitopes-on-t-cell-immunity
#13
Tracy M Josephs, Emma J Grant, Stephanie Gras
It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8 to 10 residues in length. However, this dogma has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8+ T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity...
January 31, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28134319/a-comprehensive-analysis-of-the-germline-and-expressed-tcr-repertoire-in-white-peking-duck
#14
Zhi Yang, Yi Sun, Yonghe Ma, Zhenrong Li, Yu Zhao, Liming Ren, Haitang Han, Yunliang Jiang, Yaofeng Zhao
Recently, many immune-related genes have been extensively studied in ducks, but relatively little is known about their TCR genes. Here, we determined the germline and expressed repertoire of TCR genes in White Peking duck. The genomic organization of the duck TCRα/δ, TCRγ and unconventional TCRδ2 loci are highly conserved with their counterparts in mammals or chickens. By contrast, the duck TCRβ locus is organized in an unusual pattern, (Vβ)n-Dβ-(Jβ)2-Cβ1-(Jβ)4-Cβ2, which differs from the tandem-aligned clusters in mammals or the translocon organization in some teleosts...
January 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28130403/suppression-of-lethal-autoimmunity-by-regulatory-t-cells-with-a-single-tcr-specificity
#15
Andrew G Levine, Saskia Hemmers, Antonio P Baptista, Michail Schizas, Mehlika B Faire, Bruno Moltedo, Catherine Konopacki, Marc Schmidt-Supprian, Ronald N Germain, Piper M Treuting, Alexander Y Rudensky
The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity...
January 27, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28114168/thymic-origins-of-t-cell-receptor-alloreactivity
#16
Joanna Brzostek, Nicholas R J Gascoigne
MHC restriction is a unique feature of T cell antigen recognition. Mature T cells respond to antigenic nonself peptides bound to self-MHC molecules, but a sizeable fraction of peripheral T cells can also respond to nonself peptide-MHC (pMHC) complexes in the context of transplantation. MHC specificity of the T cell receptor repertoire is shaped during thymic development. Two hypotheses have been proposed to explain MHC specificity of T cells. It has been suggested that MHC specificity is an intrinsic feature of TCR structure, mediated by the germline-encoded regions of the TCR sequence...
January 20, 2017: Transplantation
https://www.readbyqxmd.com/read/28108559/antigen-processing-in-the-endoplasmic-reticulum-is-monitored-by-semi-invariant-%C3%AE-%C3%AE-tcrs-specific-for-a-conserved-peptide-qa-1b-mhc-class-ib-ligand
#17
Jian Guan, Soo Jung Yang, Federico Gonzalez, Yuxin Yin, Nilabh Shastri
Ag processing in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP) is central to presentation of a normal peptide-MHC class I (MHC I) repertoire. Alternations in ERAAP function cause dramatic changes in the MHC I-presented peptides, which elicit potent immune responses. An unusual subset of CD8(+) T cells monitor normal Ag processing by responding to a highly conserved FL9 peptide that is presented by Qa-1(b), a nonclassical MHC Ib molecule (QFL) in ERAAP-deficient cells...
January 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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
#18
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
#19
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
#20
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...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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