Dual CD8 and TCR editing in regulatory T cells mediates HLA-A2-restricted tissue-specific homing
Type 1 diabetes (T1D) is marked by the overexpression of class I major histocompatibility complex (MHC) antigens in pancreatic islets, which are targeted by islet-specific CD8<sup>+</sup> T cells. Here, we aimed to improve regulatory T cell (Treg) infiltration into pancreatic islets by redirecting their specificity toward class I-restricted islet antigens. We functionally validated two islet-specific HLA-A2 (∗02:01)-restricted T cell receptors (TCRs), one specific for ZnT8<sub>186-194</sub> (clone D222D) and the second for IGRP<sub>265-273</sub> (clone 32), by dual-locus (TRAC/CD4) homology-directed editing. Clone D222D was peptide specific and CD8αβ dependent, while clone 32 exhibited antigen promiscuity and showed CD8α dependency. Engineered CD4<sup>to8</sup> TCR Tregs maintained stable phenotypes, in vitro suppressive function compared to their polyclonal counterparts, and showed co-receptor-dependent migration in vivo. This approach demonstrates that TCR specificity, reflected by its functional activity, is crucial for tissue-specific trafficking, paving the way to improve the efficacy of Treg therapies for T1D.
Authors
- Philippe Guillaume (ORCID: https://orcid.org/0000-0002-6340-0963)
- Oscar Alfageme-Abello (ORCID: https://orcid.org/0000-0002-9963-7137)
- Aikaterini Semilietof (ORCID: https://orcid.org/0000-0001-6799-0676)
- Laura Ermellino
- Evangelos Stefanidis (ORCID: https://orcid.org/0000-0002-8750-5954)
- Kevin Bellofatto (ORCID: https://orcid.org/0000-0001-7961-4539)
- Spiros Georgakis (ORCID: https://orcid.org/0000-0002-9398-3143)
- Matthieu Perreau (ORCID: https://orcid.org/0000-0003-2110-2244)
- Y. D. Muller
- Eleonora Pace (ORCID: https://orcid.org/0000-0002-4075-1509)
- Vincent Zoete (ORCID: https://orcid.org/0000-0002-2336-6537)
- Erica Lana
- Fanny Lebreton
- Greta Giordano-Attianese
- Qizhi Tang (ORCID: https://orcid.org/0000-0001-7313-3574)
- Constantinos Petrovas (ORCID: https://orcid.org/0000-0002-5067-5810)
- Morteza Hafezi (ORCID: https://orcid.org/0009-0005-2494-449X)
- Francesco A. Procopio
- Melita Irving
- Rebecca Cecchin
- Raphaël Porret
- Ekaterine Berishvili
- Ana Alcaraz-Serna
Institutions
- University of California, San Francisco (US)
- University Hospital of Geneva (CH)
- Ludwig Cancer Research (CH)
- Geneva College (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2026-02-01
- DOI
- https://doi.org/10.1016/j.ymthe.2026.02.028
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00