2025/11/11 by M. Francis, Winston Hibler, Michael Yarnell +5 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #CAR-T cell therapy research #Diabetes and associated disorders #vaccines and immunoinformatics approaches
paper · pdf · doi:10.1101/2025.11.10.687586
openalex publication_date 2025/11/11 · openalex created_date 2025/11/12 · openalex updated_date 2026/07/15
Abstract Progress has been made to address refractory T cell-mediated diseases with chimeric antigen receptor (CAR) T cell platforms, with the need more specifically target pathogenic cells being addressed by peptide-MHC (pMHC) CAR T cells. However, progress to date has largely been limited to peptide-MHC Class II (pMHC-II) CARs for the targeting of autoreactive CD4 T cells in multiple models. Here, we develop the first single molecule peptide-MHC Class I-β2 microglobulin CAR platform to demonstrate the proof of concept for depletion of antigen-specific CD8 T cells and compare the in vitro and in vivo functionality to a traditional scFv-based CAR that also targets the TCR. We demonstrate that while the scFv CAR is more rapidly and robustly activated by target CD8 T cells in vitro , the greater precision offered by pMHC-I CARs results in greater efficacy in multiple in vivo models. Additionally, we developed a novel adjuvanted ovalbumin vaccination with adoptive transfer model to induce type 1 diabetes (T1D) in RIP-mOVA mice using a polyclonal, polyepitopic T cell population. We demonstrate that our pMHC-I platform depletes SIINFEKL-reactive T cells and that control of the immune response to the dominant SIINFEKL epitope can control a broader antigenic response.