CD4⁺ CD25⁺ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice

Nephrotoxicity limits the use of cisplatin, a widely used chemotherapeutic agent for treatment of various malignancies. Overall, CD4⁺ T cells mediate cisplatin-induced renal injury; however, the CD4⁺ CD25 ⁺ regulatory T-cell subset (CD4⁺ CD25⁺ Treg) has broad suppressive effects on many different cell types. In this study, we determined whether CD4⁺ CD25⁺ Treg cells had protective effects against cisplatin-induced acute renal injury in nu/nu mice that lack mature T cells. In these mice, there was marked attenuation of the decreased survival, renal dysfunction and tubular injury, renal tumor necrosis factor-α, and interleukin-1Β cytokine levels. Furthermore, renal macrophage accumulation was reduced in CD4⁺ CD25⁺ Treg cell-adoptive transferred nu/nu mice compared with control mice. Infusion of CD4⁺ CD25⁺ Treg cells into wild-type Balb/c mice reduced serum blood urea nitrogen and creatinine levels equivalent to those in nu/nu mice and extended their survival time after cisplatin injection. In contrast, depletion of CD4⁺ CD25⁺ Treg cells in wild-type mice exacerbated kidney injury after cisplatin administration. Transcription factor Foxp3-positive cells (Treg cells) were detected in the kidneys of nu/nu mice after cisplatin injection. Our results suggest that CD4⁺ CD25 ⁺ Treg cells directly affect cisplatin nephrotoxicity and their modulation represents an additional treatment strategy.