BHLHE40 Orchestrates Effector Tissue‐Resident Memory CD8 ⁺ T Cells and Limits Long‐Term Survival of Kidney Graft

ABSTRACT 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 differentiation and effector function, thereby driving rejection in allo‐transplantation. In TLSs, TGF‐β orchestrated BHLHE40 expression in T _RM and effector T _RM differentiation. Our findings identified an effector subset of T _RM as CD49a ⁺ PD1 ^hi CD8 ⁺ T _RM , and highlighted a BHLHE40‐orchestrated, resident immune component, rather than circulating cells, as a major contributor to allograft rejection.