biostudies-literatureYou HNational Natural Science Foundation of ChinaChangzhou Sci & Tech ProgramNational Natural Science Foundation of China (National Science Foundation of China)National Science Foundation of China | Key Programme356-370https://www.ebi.ac.uk/biostudies/studies/S-EPMC11955531biostudies-literatureUnknown22(4)T-cell receptor (TCR) γδ-expressing cells are conserved lymphocytes of innate immunity involved in first-line defense and immune surveillance. TCRγδ recognizes protein/nonprotein ligands without the help of the major histocompatibility complex (MHC), especially via direct binding to protein ligands, which is dependent primarily on the δ chain complementary determining region 3 (CDR3δ). However, the mechanism of protein‒antigen recognition by human γδ TCRs remains poorly defined. We hypothesize that γδ TCRs recognize self-proteins expressed ectopically on the cell membrane that are derived from intracellular components under stress. Here, we mapped 16 intercellular self-proteins among 21,000 proteins with a huProteinChip as putative ligands for Vδ1/Vδ2 TCRs, 13 for Vδ1 TCRs and 3 for Vδ2 TCCellular & molecular immunologyγδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition.PMC11955531323007453227091582103319U20A2037482071791Hu YZhang JCai MChen MChen HDong QPang YDong PZhao YWang SHe WZhang XTeng DLiu CHan JYou HXu Yfalseγδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition.T-cell receptor (TCR) γδ-expressing cells are conserved lymphocytes of innate immunity involved in first-line defense and immune surveillance. TCRγδ recognizes protein/nonprotein ligands without the help of the major histocompatibility complex (MHC), especially via direct binding to protein ligands, which is dependent primarily on the δ chain complementary determining region 3 (CDR3δ). However, the mechanism of protein‒antigen recognition by human γδ TCRs remains poorly defined. We hypothesize that γδ TCRs recognize self-proteins expressed ectopically on the cell membrane that are derived from intracellular components under stress. Here, we mapped 16 intercellular self-proteins among 21,000 proteins with a huProteinChip as putative ligands for Vδ1/Vδ2 TCRs, 13 for Vδ1 TCRs and 3 for Vδ2 TC2025-01-01T00:00:00Z2025 Apr2026-06-02T18:10:16.841Z2025-07-11T03:04:00.556ZS-EPMC119555313993981610.1038/s41423-025-01258-x