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bioRxiv · 10.1101/2025.03.17.643496

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

Porret, R.·Lebreton, F.·Stefanidis, E.·Semilietof, A.·Guillaume, P.·Georgakis, S.·Pace, E.·Alfageme-Abello, O.·Alcaraz-Serna, A.·Ermellino, L.·Cecchin, R.·Lana, E.·Giordano-Attianese, G.·Zoete, V.·Petrovas, C.·Irving, M.·Berishvili, E.·Tang, Q.·Muller, Y. D.
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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 CD8{beta} dependent while clone 32 exhibited antigen promiscuity and showed CD8 dependency. Engineered CD4to8 TCR Tregs maintained stable phenotypes, suppressed significantly better than their polyclonal counterpart, 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.

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Porret, R., Lebreton, F., Stefanidis, E., Semilietof, A., Guillaume, P., Georgakis, S., Pace, E., Alfageme-Abello, O., Alcaraz-Serna, A., Ermellino, L., Cecchin, R., Lana, E., Giordano-Attianese, G., Zoete, V., Petrovas, C., Irving, M., Berishvili, E., Tang, Q., Muller, Y. D.. 2025-03-18. Redirecting TCR specificity in regulatory T cells toward class I HLA antigens mediates tissue-specific homing. https://doi.org/10.1101/2025.03.17.643496

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