biostudies-literatureLi Jkey R&D program of department of science and technology of Hubei province, ChinaNon-profit Central Research Institute Fund of ChineseHubei Province Science Fund for Distinguished Young ScholarsHubei Provincial Department of Science and Technology, Hubei Provincial Key Research and Development ProgramNational Natural Science Foundation of Chinae20518https://www.ebi.ac.uk/biostudies/studies/S-EPMC12915110biostudies-literatureUnknown13(10)Tissue-resident memory T cells (T_RM), which function against tumors, infections, and non-self antigens in organ transplantation, exhibit both effector and memory functionality. However, the homeostasis and differentiation of T_RM is not clear. Using a murine kidney transplant model for long-term observation, our single-cell and spatial transcriptomics showed that CD49a⁺PD1^hi CD8⁺ T_RM exhibited an effector phenotype with enhanced cytotoxicity at a later stage. This subset might mature from a CXCR6^hi precursor-like state with proliferation capacity in tertiary lymphoid structures (TLSs) in allografts. Mechanically, BHLHE40 is required for CD49a⁺PD1^hi CD8⁺ T_RM differentiatioAdvanced science (Weinheim, Baden-Wurttemberg, Germany)BHLHE40 Orchestrates Effector Tissue-Resident Memory CD8<sup>+</sup> T Cells and Limits Long-Term Survival of Kidney Graft.PMC1291511082471810823717942023BCB013822718072023-PT320-072022CFA0572022BCA015Liu JLi JPan TChen ZLan PYang BMa ZTang DZhou XXie BfalseBHLHE40 Orchestrates Effector Tissue-Resident Memory CD8<sup>+</sup> T Cells and Limits Long-Term Survival of Kidney Graft.Tissue-resident memory T cells (T_RM), which function against tumors, infections, and non-self antigens in organ transplantation, exhibit both effector and memory functionality. However, the homeostasis and differentiation of T_RM is not clear. Using a murine kidney transplant model for long-term observation, our single-cell and spatial transcriptomics showed that CD49a⁺PD1^hi CD8⁺ T_RM exhibited an effector phenotype with enhanced cytotoxicity at a later stage. This subset might mature from a CXCR6^hi precursor-like state with proliferation capacity in tertiary lymphoid structures (TLSs) in allografts. Mechanically, BHLHE40 is required for CD49a⁺PD1^hi CD8⁺ T_RM differentiatio2026-01-01T00:00:00Z2026 Feb2026-07-16T06:51:51.721Z2026-07-09T10:41:24.828ZS-EPMC129151104148650710.1002/advs.202520518