Selective immunotargeting of diabetogenic CD4 T cells by genetically redirected T cells

Authors

  • Shira Perez,

    1. Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona, Israel
    2. Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
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  • Sigal Fishman,

    1. Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona, Israel
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  • Amos Bordowitz,

    1. Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona, Israel
    2. Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
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  • Alon Margalit,

    1. Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona, Israel
    2. Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
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  • F. Susan Wong,

    1. Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff, UK
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  • Gideon Gross

    Corresponding author
    1. Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona, Israel
    2. Department of Biotechnology, Tel-Hai College, Upper Galilee, Israel
    • Correspondence: Gideon Gross, Laboratory of Immunology, MIGAL Galilee Research Institute, Kiryat Shmona 11016, Israel. Email: gidi@migal.org.il

      Senior author: Gideon Gross

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Summary

The key role played by islet-reactive CD8 and CD4 T cells in type 1 diabetes calls for new immunotherapies that target pathogenic T cells in a selective manner. We previously demonstrated that genetically linking the signalling portion of CD3-ζ onto the C-terminus of β2-microglobulin and an autoantigenic peptide to its N-terminus converts MHC-I complexes into functional T-cell receptor-specific receptors. CD8 T cells expressing such receptors specifically killed diabetogenic CD8 T cells, blocked T-cell-induced diabetes in immunodeficient NOD.SCID mice and suppressed disease in wild-type NOD mice. Here we describe the immunotargeting of CD4 T cells by chimeric MHC-II receptors. To this end we chose the diabetogenic NOD CD4 T-cell clone BDC2.5, which recognizes the I-Ag7-bound 1040-31 mimotope. We assembled several constructs encoding I-Ag7 α- and β-chains, the latter carrying mim or hen egg lysozyme peptide as control, each supplemented with CD3-ζ intracellular portion, either with or without its transmembrane domain. Following mRNA co-transfection of reporter B3Z T cells and mouse CD8 and CD4 T cells, these constructs triggered robust activation upon I-Ag7 cross-linking. A BDC2.5 T-cell hybridoma activated B3Z transfectants expressing the mimotope, but not the control peptide, in both configurations. Potent two-way activation was also evident with transgenic BDC2.5 CD4 T cells, but peptide-specific activation required the CD3-ζ transmembrane domain. Chimeric MHC-II/CD3-ζ complexes therefore allow the selective immunotargeting of islet-reactive CD4 T cells, which take part in the pathogenesis of type 1 diabetes.

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