| First Author | Porret R | Year | 2025 |
| Journal | Sci Transl Med | Volume | 17 |
| Issue | 790 | Pages | eadr8941 |
| PubMed ID | 40106579 | Mgi Jnum | J:370740 |
| Mgi Id | MGI:8169227 | Doi | 10.1126/scitranslmed.adr8941 |
| Citation | Porret R, et al. (2025) T cell receptor precision editing of regulatory T cells for celiac disease. Sci Transl Med 17(790):eadr8941 |
| abstractText | Celiac disease, a gluten-sensitive enteropathy, demonstrates a strong human leukocyte antigen (HLA) association, with more than 90% of patients carrying the HLA-DQ2.5 allotype. No therapy is available for the condition except for a lifelong gluten-free diet. To address this gap, we explored the therapeutic potential of regulatory T cells (T(regs)). By orthotopic replacement of T cell receptors (TCRs) through homology-directed repair, we generated gluten-reactive HLA-DQ2.5-restricted CD4(+) engineered (e) T effector cells (T(effs)) and eT(regs) and performed in vivo experiments in HLA-DQ2.5 transgenic mice. Of five validated TCRs, TCRs specific for two immunodominant and deamidated gluten epitopes (DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2) were selected for further evaluation. CD4(+) eT(effs) exposed to deamidated gluten through oral gavage colocalized with dendritic and B cells in the Peyer's patches and gut-draining lymph nodes and specifically migrated to the intestine. The suppressive function of human eT(regs) correlated with high TCR functional activity. eT(regs) specific for one epitope suppressed the proliferation and gut migration of CD4(+) eT(effs) specific for the same and the other gluten epitope, demonstrating bystander suppression. The suppression requires an antigen-specific activation of eT(regs) given that polyclonal T(regs) failed to suppress CD4(+) eT(effs). These findings highlight the potential of gluten-reactive eT(regs) as a therapeutic for celiac disease. |
