Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

HIGHLY DIVERSE TCRalpha CHAIN REPERTOIRE OF PRE-IMMUNE CD8+ T CELLS REVEALS NEW INSIGHTS IN GENE RECOMBINATION

ABSTRACT: By sequencing tens of millions of TCR? chain transcripts from naïve mouse CD8+ T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compatible with sequential coordinate gene recombination, but rather with a model in which contraction and DNA looping in the TCR?? locus provide equal access to TRAV and TRAJ gene segments, similar to that demonstrated for IgH gene recombination High-throughput sequencing of entire TCRa repertoire from C57Bl/6 mice

ORGANISM(S): Mus musculus

SUBMITTER: Brian Stevenson

PROVIDER: E-GEOD-35626 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Highly diverse TCRα chain repertoire of pre-immune CD8⁺ T cells reveals new insights in gene recombination.

Genolet Raphael R Stevenson Brian J BJ Farinelli Laurent L Osterås Magne M Luescher Immanuel F IF

The EMBO journal 20120228 7

Although the T-cell receptor αδ (TCRαδ) locus harbours large libraries of variable (TRAV) and junctional (TRAJ) gene segments, according to previous studies the TCRα chain repertoire is of limited diversity due to restrictions imposed by sequential coordinate TRAV-TRAJ recombinations. By sequencing tens of millions of TCRα chain transcripts from naive mouse CD8(+) T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compati ...[more]

PMID: 22373576

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

Dataset Information

HIGHLY DIVERSE TCRalpha CHAIN REPERTOIRE OF PRE-IMMUNE CD8+ T CELLS REVEALS NEW INSIGHTS IN GENE RECOMBINATION

Publications

Highly diverse TCRα chain repertoire of pre-immune CD8⁺ T cells reveals new insights in gene recombination.

Similar Datasets

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