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

Shira Perez, Sigal Fishman, Amos Bordowitz, Alon Margalit, F. Susan Wong, Gideon Gross

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish
Pages (from-to)609-617
Number of pages9
Issue number4
StatePublished - 1 Dec 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 John Wiley & Sons Ltd.


  • Adoptive T-cell immunotherapy
  • Chimeric receptors
  • T-cell activation
  • Type 1 diabetes
  • mRNA transfection


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