T‐Cell Remodeling in Renal Fibrosis: From Acute Injury to Chronic Kidney Disease

ABSTRACT Renal fibrosis is a final common pathway in chronic kidney disease (CKD), yet available therapies rarely reverse established scarring. T lymphocytes are now recognized as dynamic regulators of this process rather than simple inflammatory bystanders. This Review integrates evidence from experimental kidney injury models, human biopsy studies, single‐cell RNA sequencing, spatial transcriptomics, and biomarker analyses to establish a three‐stage framework for T‐cell remodeling during the transition from acute kidney injury (AKI) to CKD. In Stage 1, chemokine gradients recruit T cells into injured kidney tissue, where effector activation, cytotoxic injury, paracrine inflammation, and metabolic adaptation shape early outcomes. In Stage 2, unresolved injury favors immune imbalance, including T helper 17/regulatory T cell disequilibrium, dendritic cell–T cell crosstalk, and tertiary lymphoid structure formation. In Stage 3, exhausted and tissue‐resident memory T cells coexist with cellular senescence, mitochondrial stress, and profibrotic signaling. Across these stages, recurrent pathways, including PI3K/Akt/mTORC1, TGF‐β/Smad3, IFN‐γ/STAT1, and IL‐15/CD122, connect immune remodeling to structural fibrosis in a manner that depends on timing, cell type, and tissue context. This framework may help refine staging based on biomarkers and guide the development of therapies matched to the dominant immune program.