Redirecting TCR specificity in regulatory T cells toward class I HLA antigens mediates tissue-specific homing

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Abstract

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+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 public islet specific HLA-A2 (*02:01) restricted TCRs, one specific for ZnT8186-194(clone D222D), the second for IGRP265-273(clone 32) by dual locus (TRAC/CD4) homology-directed editing. Clone D222D was peptide-specific and CD8β dependent while clone 32 exhibited antigen promiscuity and showed CD8α dependency. Engineered CD4to8TCR Tregs maintained stable phenotypes, suppressed significantly better than their polyclonal counterpart, and showed co-receptor-dependent migrationin 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.

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