Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumour-specific peptides is a promising immunotherapy. However, these TCR-T cells can cross-react with off-target peptides, leading to severe autoimmune toxicities. Current efforts focus on identifying TCRs with reduced cross-reactivity. Here we show that T cell cross-reactivity can be controlled by the co-signalling molecules CD5, CD8 and CD4, without modifying the TCR. We find the largest reduction in cytotoxic T cell cross-reactivity by knocking out CD8 and expressing CD4. Cytotoxic T cells engineered with a CD8→CD4 co-receptor switch show reduced cross-reactivity to random and positional scanning peptide libraries, as well as to self-peptides, while maintaining their on-target potency. Therefore, co-receptor switching generates super selective T cells that reduce the risk of lethal off-target cross-reactivity and offers a universal method to enhance the safety of T cell immunotherapies for potentially any TCR.
Journal article
2026-04-01T00:00:00+00:00
10
753 - 764
11
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
T-Lymphocytes, CD8-Positive T-Lymphocytes, T-Lymphocytes, Cytotoxic, Animals, Humans, Mice, Peptides, Peptide Library, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Signal Transduction, Cross Reactions, Cell Engineering, CD4 Antigens, CD8 Antigens