The key role played by islet-reactive CD8 and CD4 T cells in type 1 diabetes calls for new immunotherapies which target pathogenic T cells in a selective manner. We previously demonstrated that genetically linking the signaling 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 th... More
The key role played by islet-reactive CD8 and CD4 T cells in type 1 diabetes calls for new immunotherapies which target pathogenic T cells in a selective manner. We previously demonstrated that genetically linking the signaling 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 thus allow the selective immunotargeting of islet-reactive CD4 T cells which take part in the pathogenesis of type 1 diabetes. This article is protected by copyright. All rights reserved.
