Renal ischemia/reperfusion injury often progresses to chronic kidney disease (CKD) due to maladaptive repair processes and persistent inflammation. IL-17A producing γδT cells regulate inflammation, tissue repair, and immune responses in various organs, but whether these functions pertain to maladaptive repair after renal ischemia/reperfusion remains unclear.

A single-cell dataset encompassing multiple time points (7 to 28 days) post-IRI was obtained from the public GEO database for analysis. The immune abundance analysis, immune-related gene analysis, enrichment analysis, and cell-cell chat analyses were performed on both single-cell and bulk RNA-seq data. Then, a human CKD dataset from GEO database with parameters of kidney function, estimated glomerular filtration rate (eGFR), degree of renal tubulointerstitial fibrosis, as well as CKD progression were utilized to investigate the clinical relevance of γδ T cells in CKD.

Here, we found that the proportion of γδT cells were increased in kidneys with maladaptive process after ischemia reperfusion injuries and positively correlated with fibrotic levels. γδT cells highly express chemokine receptors (e.g., CCR2, CXCR6) but exhibit low levels of tissue-resident markers, particularly after renal ischemia-reperfusion injury. Meanwhile, chemokines are predominantly secreted by infiltrating and proliferating macrophages, suggesting that the increase in γδT cell numbers following renal ischemia-reperfusion injury may be primarily driven by macrophage recruitment. Next, γδT cells exhibit an IL-17A-producing phenotype in renal tissues following ischemia-reperfusion injury, characterized by the expression of IL-17A and its key transcription factors, while showing minimal expression of IFN-γ. The cell-cell chat analysis indicated that the primary effector cells of γδT cells are neutrophils, which specifically express IL17RA compared to other cell types.

Overall, the γδT cell-neutrophil axis may play a critical role in renal ischemia-reperfusion injury, and targeting this axis could provide a novel therapeutic strategy for renal ischemia/reperfusion injury.