NKT cell deficiency exacerbates adenine-induced renal fibrosis through enhanced Treg infiltration and TGF-β expression.

Abstract

Natural killer T (NKT) cells are immunoregulatory lymphocytes known for their roles in infection and tumor immunity, but their involvement in renal fibrosis remains unclear. In this study, we investigated the role of NKT cells in adenine-induced renal fibrosis using CD1d-knockout (CD1dKO) mice, which lack NKT cells, and wild-type (WT) controls. Both CD1dKO and WT mice developed renal dysfunction following 5 wk of being fed an adenine-rich diet; however, CD1dKO mice exhibited significantly greater weight loss, elevated serum blood urea nitrogen and creatinine levels, and increased expression of fibrosis- and inflammation-related genes, including Acta2, Col1a1, Tgfb1, Fn1, and Il1b, Il6, Tnf. Histological analysis revealed markedly enlarged fibrotic areas in the kidneys of CD1dKO mice. Flow cytometry demonstrated increased infiltration of CD25⁺ Foxp3⁺ regulatory T cells (Tregs) in CD1dKO mice compared with WT controls. Given that Tregs are a major source of TGF-β, these results suggest that the absence of NKT cells promotes a profibrotic immune environment through enhanced Treg accumulation and TGF-β expression. Our findings showed that NKT cells play a protective role in limiting renal fibrosis progression by modulating immune cell infiltration, particularly enhanced Treg accumulation, and cytokine production. Targeting NKT cell pathways may represent a novel therapeutic approach for the treatment of chronic kidney disease and fibrosis.NEW & NOTEWORTHY This study reveals a protective role for natural killer T (NKT) cells in adenine-induced renal fibrosis. Using CD1d-deficient mice lacking NKT cells, we demonstrate that their absence leads to worsened fibrosis, heightened inflammation, and increased regulatory T cell infiltration. These findings suggest that NKT cells mitigate fibrotic progression by modulating immune responses and highlight a potential therapeutic target in chronic kidney disease.