BHLHE40 Orchestrates Effector Tissue‐Resident Memory CD8 ⁺ 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 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.