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https://www.readbyqxmd.com/read/29176645/t-cell-receptor-%C3%AE-chains-display-abnormal-shortening-and-repertoire-sharing-in-type-1-diabetes
#1
Iria Gomez-Tourino, Yogesh Kamra, Roman Baptista, Anna Lorenc, Mark Peakman
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2 × 108 TCRB sequences of circulating naive, central memory, regulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection...
November 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29106410/generation-of-higher-affinity-t-cell-receptors-by-antigen-driven-differentiation-of-progenitor-t-cells-in-vitro
#2
Thomas M Schmitt, David H Aggen, Kumiko Ishida-Tsubota, Sebastian Ochsenreither, David M Kranz, Philip D Greenberg
Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low-avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs...
November 6, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29103899/perturbation-of-the-t-cell-receptor-repertoire-occurs-with-increasing-age-in-dogs
#3
Angela Holder, Samantha M Mirczuk, Robert C Fowkes, Donald B Palmer, Richard Aspinall, Brian Catchpole
Immunosenescence is the gradual deterioration in immune system function associated with ageing. This decline is partly due to involution of the thymus, which leads to a reduction in the output of naive T cells into the circulating lymphocyte pool. Expansion of existing naive and memory T cell populations, to compensate for the reduction in thymic output, can lead to reduced diversity in the T cell repertoire with increasing age, resulting in impairment of immune responses to novel antigenic challenges, such as during infection and vaccination...
October 28, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28977923/integrated-analysis-of-somatic-mutations-and-immune-microenvironment-of-multiple-regions-in-breast-cancers
#4
Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Yuji Ikeda, Yasuo Miyoshi, Yusuke Nakamura
Next-generation sequencing technology enables us to analyze the complexity of intra- and inter-tumoral heterogeneity, which may influence to prognosis of cancer patients. In this study, we collected surgically-resected tumor tissues from five breast cancer patients and characterized three different portions of individual tumors through somatic mutation analysis by whole exome sequencing, T cell receptor beta (TCRB) repertoire analysis of tumor-infiltrating lymphocytes (TILs), and the expression analysis of immune-related genes at 15 different sites...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28830578/characterization-of-demodex-musculi-infestation-associated-comorbidities-and-topographic-distribution-in-a-mouse-strain-with-defective-adaptive-immunity
#5
Melissa A Nashat, Kerith R Luchins, Michelle L Lepherd, Elyn R Riedel, Joanna N Izdebska, Neil S Lipman
A colony of B6.Cg-Rag1tm1Mom Tyrp1B-w Tg(Tcra,Tcrb)9Rest (TRP1/TCR) mice presented with ocular lesions and ulcerative dermatitis. Histopathology, skin scrapes, and fur plucks confirmed the presence of Demodex spp. in all clinically affected and subclinical TRP1/TCR mice examined (n = 48). Pasteurella pneumotropica and Corynebacterium bovis, both opportunistic pathogens, were cultured from the ocular lesions and skin, respectively, and bacteria were observed microscopically in abscesses at various anatomic locations (including retroorbital sites, tympanic bullae, lymph nodes, and reproductive organs) as well as the affected epidermis...
August 1, 2017: Comparative Medicine
https://www.readbyqxmd.com/read/28811963/characterization-of-the-cryoablation-induced-immune-response-in-kidney-cancer-patients
#6
Taigo Kato, Tomoyuki Iwasaki, Motohide Uemura, Akira Nagahara, Hiroki Higashihara, Keigo Osuga, Yuji Ikeda, Kazuma Kiyotani, Jae-Hyun Park, Norio Nonomura, Yusuke Nakamura
Cryoablation is one of treatment modalities for kidney cancer and is expected to induce strong local immune responses as well as systemic T-cell-mediated immune reactions that may lead to the regression of distant metastatic lesions. Thus, the characterization of T cell repertoire and immune environment in tumors before and after treatment should contribute to the better understanding of the cryoablation-induced anticancer immune responses. In this study, we collected tumor tissues from 22 kidney cancer patients, before cryoablation and at 3 mo after cryoablation...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28706143/integrated-analysis-of-somatic-mutations-and-immune-microenvironment-of-multiple-regions-in-breast-cancers
#7
Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Yuji Ikeda, Yasuo Miyoshi, Yusuke Nakamura
Next-generation sequencing technology enables us to analyze the complexity of intra- and inter-tumoral heterogeneity, which may influence to prognosis of cancer patients. In this study, we collected surgically-resected tumor tissues from five breast cancer patients and characterized three different portions of individual tumors through somatic mutation analysis by whole exome sequencing, T cell receptor beta (TCRB) repertoire analysis of tumor-infiltrating lymphocytes (TILs), and the expression analysis of immune-related genes at 15 different sites...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28637900/activation-of-mouse-tcrb-uncoupling-runx1-function-from-its-cooperative-binding-with-ets1
#8
Jiang-Yang Zhao, Oleg Osipovich, Olivia I Koues, Kinjal Majumder, Eugene M Oltz
T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β (Tcrb) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites...
August 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28620653/successive-annual-influenza-vaccination-induces-a-recurrent-oligoclonotypic-memory-response-in-circulating-t-follicular-helper-cells
#9
Ramin Sedaghat Herati, Alexander Muselman, Laura Vella, Bertram Bengsch, Kaela Parkhouse, Daniel Del Alcazar, Jonathan Kotzin, Susan A Doyle, Pablo Tebas, Scott E Hensley, Laura F Su, Kenneth E Schmader, E John Wherry
T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38...
February 2017: Science Immunology
https://www.readbyqxmd.com/read/28535950/aging-related-changes-in-human-t-cell-repertoire-over-20years-delineated-by-deep-sequencing-of-peripheral-t-cell-receptors
#10
Kengo Yoshida, John B Cologne, Kismet Cordova, Munechika Misumi, Mika Yamaoka, Seishi Kyoizumi, Tomonori Hayashi, Harlan Robins, Yoichiro Kusunoki
Recent deep sequencing studies on T-cell receptor (TCR) repertoire have provided robust data to characterize diversity of T-cell immune responsiveness to a wide variety of peptide antigens, including viral and tumor antigens. The human TCR repertoire declines with age, but this decline has not been fully investigated longitudinally in individuals. Using a deep sequencing approach, we analyzed TCRβ repertoires longitudinally over approximately 20years, with ages ranging from 23 to 50years at the start (23 to 65years overall), in peripheral-blood CD4 and CD8 T-cell populations that were collected and cryopreserved 3 times at intervals of approximately 10years from each of 6 healthy adults (3 men and 3 women)...
October 1, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28508570/a-new-transcript-in-the-tcrb-locus-unveils-the-human-ortholog-of-the-mouse-pre-d%C3%A3-1-promoter
#11
Bernard Lethé, Sylvia Snauwaert, Orian Bricard, David Schröder, Tiphanie Gomard, Gérald Hames, Catherine Muller, Christophe Lurquin, Emilie Gauthy, Ahmed Essaghir, Bart Vandekerckhove, Pierre G Coulie
INTRODUCTION: While most transcripts arising from the human T Cell Receptor locus reflect fully rearranged genes, several germline transcripts have been identified. We describe a new germline transcript arising from the human TCRB locus. METHODS: cDNA sequencing, promoter, and gene expression analyses were used to characterize the new transcript. RESULTS: The new germline transcript encoded by the human TCRB locus consists of a new exon of 103 bp, which we named TRBX1 (X1), spliced with the first exon of gene segments Cß1 or Cß2...
September 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28320875/gata3-abundance-is-a-critical-determinant-of-t-cell-receptor-%C3%AE-allelic-exclusion
#12
Chia-Jui Ku, JoAnn M Sekiguchi, Bharat Panwar, Yuanfang Guan, Satoru Takahashi, Keigyou Yoh, Ivan Maillard, Tomonori Hosoya, James Douglas Engel
Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor β (TCRβ) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCRβ protein...
June 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28316595/effects-of-copper-addition-on-copper-resistance-antibiotic-resistance-genes-and-intl1-during-swine-manure-composting
#13
Yanan Yin, Jie Gu, Xiaojuan Wang, Wen Song, Kaiyu Zhang, Wei Sun, Xin Zhang, Yajun Zhang, Haichao Li
Copper is one of the most abundant heavy metals present in swine manure. In this study, a laboratory-scale aerobic composting system was amended with Cu at three levels (0, 200, and 2000 mg kg(-1), i.e., control, Cu200, and Cu2000 treatments, respectively) to determine its effect on the fate of copper resistance genes [copper resistance genes (CRGs): pcoA, cusA, copA, and tcrB], antibiotic resistance genes [antibiotic resistance genes (ARGs): erm(A) and erm(B)], and intl1. The results showed that the absolute abundances of pcoA, tcrB, erm(A), erm(B), and intl1 were reduced, whereas those of copA and cusA increased after swine manure composting...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28244489/chromosome-choice-for-initiation-of-v-d-j-recombination-is-not-governed-by-genomic-imprinting
#14
Claudia Gebert, Lauren Correia, Zhenhu Li, Howard T Petrie, Paul E Love, Karl Pfeifer
V-(D)-J recombination generates the antigen receptor diversity necessary for immune cell function, while allelic exclusion ensures that each cell expresses a single antigen receptor. V-(D)-J recombination of the Ig, Tcrb, Tcrg and Tcrd antigen receptor genes is ordered and sequential so that only one allele generates a productive rearrangement. The mechanism controlling sequential rearrangement of antigen receptor genes, in particular how only one allele is selected to initiate recombination while at least temporarily leaving the other intact, remains unresolved...
May 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28212502/a-new-mechanism-shapes-the-na%C3%A3-ve-cd8-t-cell-repertoire-the-selection-for-full-diversity
#15
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 clonal sizes...
May 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28150718/distinct-requirement-of-runx-complexes-for-tcr%C3%AE-enhancer-activation-at-distinct-developmental-stages
#16
Wooseok Seo, Sawako Muroi, Kaori Akiyama, Ichiro Taniuchi
A TCRβ enhancer, known as the Eβ enhancer, plays a critical role in V(D)J recombination and transcription of the Tcrb gene. However, the coordinated action of trans-acting factors in the activation of Eβ during T cell development remains uncharacterized. Here, we characterized the roles of Runx complexes in the regulation of the Eβ function. A single mutation at one of the two Runx binding motifs within the Eβ severely impaired Tcrb activation at the initiation phase in immature thymocytes. However, TCRβ expression level in mature thymocytes that developed under such a single Runx site mutation was similar to that of the control...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28137913/chromatin-domain-organization-of-the-tcrb-locus-and-its-perturbation-by-ectopic-ctcf-binding
#17
Pratishtha Rawat, Manisha Jalan, Ananya Sadhu, Abhilasha Kanaujia, Madhulika Srivastava
CTCF-mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions among CTCF binding sites (CBS) at the murine TCRb locus to discern the role of CTCF-mediated interactions in the regulation of transcription and VDJ recombination. Chromosome conformation capture analysis revealed thymocyte-specific long-range intrachromosomal interactions among various CBS across the locus that were relevant for defining the limit of the enhancer Eb-regulated recombination center (RC) and for facilitating the spatial proximity of TCRb variable (V) gene segments to the RC...
May 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28093487/a-pilot-trial-of-the-combination-of-vemurafenib-with-adoptive-cell-therapy-in-patients-with-metastatic-melanoma
#18
Drew C Deniger, Mei Li M Kwong, Anna Pasetto, Mark E Dudley, John R Wunderlich, Michelle M Langhan, Chyi-Chia Richard Lee, Steven A Rosenberg
PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF(V600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration...
January 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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...
February 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27880974/deep-sequencing-of-the-tcr-%C3%AE-repertoire-of-human-forkhead-box-protein-3-foxp3-and-foxp3-t-cells-suggests-that-they-are-completely-distinct-and-non-overlapping
#20
A Golding, S Darko, W H Wylie, D C Douek, E M Shevach
Maintenance of peripheral tolerance requires a balance between autoreactive conventional T cells (Tconv ) and thymically derived forkhead box protein 3 (FoxP3)(+) regulatory T cells (tTregs ). Considerable controversy exists regarding the similarities/differences in T cell receptor (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...
April 2017: Clinical and Experimental Immunology
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