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Proteomics analysis between T cell lysate and T cell microvilli-derived particles

ABSTRACT: Although T cell activation is closely linked to internalization of the T cell antigen receptor (TCR), relatively few studies have examined the release of TCRs via shedding of T cell microvilli following physical interaction with cognate antigen-presenting cells. In this study, we investigated the physiological implications of the release of TCRs and other external membrane components. We term this event “trogocytic molting”, as it occurs through a combined process of trogocytosis and enzymatic vesiculation of microvillar membrane structures. Surprisingly, in contrast to TCR internalization, this event leads to rapid upregulation of surface TCRs and remarkable metabolic reprogramming of cholesterol and fatty acids synthesis to meet the demands of clonal expansion, which drives multiple rounds of division and cell survival. To elucidate a potential mechanism for how trogocytic molting of microvilli enhances T-cell proliferation, purified TISs obtained from activated naive CD3+ T cells were subjected to LC-MS/MS analysis to identify TISs-enriched functional proteins.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell, Lymph Node

SUBMITTER: Wonchang Soh

LAB HEAD: Chang-Duk Jun

PROVIDER: PXD041442 | Pride | 2023-05-09

REPOSITORIES: Pride

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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.

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Proteomics analysis between T cell lysate and T cell microvilli-derived particles

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