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Reducing the affinity of the CAR has been shown to improve the function of effector CAR\u2010T cells by limiting their activation\u2010induced exhaustion while preserving their capacity for serial killing of antigen\u2010rich tumor cells. CAR technologies are increasingly being applied to regulatory T cell (Treg)\u2013based immunotherapies as well. However, the impact of CAR affinity on Treg biology and function remains poorly understood. To address this question, we transduced purified human Tregs with second\u2010generation CAR constructs bearing scFvs with varying affinities toward HLA\u2010A2 and compared their properties both in vitro and in vivo. High\u2010affinity (HA) CAR\u2010Tregs displayed higher avidity and more pronounced CAR downregulation upon antigen engagement. In contrast, low\u2010affinity (LA) CAR\u2010Tregs exhibited enhanced antigen\u2010specific activation and superior suppressive capacity. These differences were confirmed using human and mouse precision\u2010cut liver slices and a xenogeneic graft\u2010versus\u2010host disease (GVHD) murine model. LA CAR\u2010Tregs exhibited greater accumulation\/persistence, delayed GVHD onset, and improved survival than HA CAR\u2010Tregs. Our findings, indicating that CAR affinity strongly influences CAR\u2010Treg function, provide important considerations for the optimization of engineered Treg therapies and the benchmarking of existing cell products.<\/jats:p>","DOI":"10.1002\/eji.70226","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:18:12Z","timestamp":1781695092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tuning the Affinity of Chimeric Antigen Receptors Enhances the Function of Human Engineered Regulatory T Cells"],"prefix":"10.1002","volume":"56","author":[{"given":"Ada Sera","family":"Kurt","sequence":"first","affiliation":[{"name":"Roger Williams Institute of Liver Studies School of Immunology &amp; Microbial Sciences (SIMS) King's College London University and King's College Hospital  London 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