Abstract Acute kidney injury (AKI) can progress to chronic kidney disease (CKD) in the setting of maladaptive repair characterized by tubular atrophy, inflammation, and fibrosis. Programmed cell death is a key driver of proximal tubule (PT) loss, yet how immune infiltration promotes tubular injury and death remains incompletely understood. Using a mouse model of maladaptive repair, we integrated bulk and single-cell RNA sequencing with immunohistochemistry and protein analyses to define immune-epithelial interactions during AKI-to-CKD transition. Injured kidneys exhibited loss of healthy PTs, expansion of injured PT subsets, and late-stage T cell accumulation. Apoptotic and necroptotic signaling pathways were markedly upregulated, particularly in VCAM1+ PT cells. Cell-cell interaction analysis identified macrophage-derived Cxcl16 as the dominant chemokine mediating recruitment of Cxcr6 + T cells. Genetic deletion of Cxcr6 reduced renal T cell accumulation, cytotoxic effector expression, and activation of apoptotic (cleaved caspase-3, Bax) and necroptotic signaling (MLKL, phospho-MLKL) in PT cells. Accordingly, Cxcr6 −/− mice displayed preserved PT differentiation, reduced fibrosis, and improved renal function. Together, these findings identify Cxcr6 + T cells as key mediators of immune-driven tubular cell death during maladaptive repair and suggest that targeting the CXCL16-CXCR6 axis may mitigate tubular injury and slow AKI-to-CKD progression.
Li et al. (2026) studied this question.