ROS-CCL5 axis recruits CD8 T lymphocytes promoting the apoptosis of granulosa cells in diminished ovary reserve.

Follicular atresia was initiated with the apoptosis of granulosa cells (GCs) mostly mediated by oxidative stress (OS). Our previous studies found that the number of CD8 T cells and proportion of CD8/CD4 T cells increased in the follicles of diminished ovary reserve (DOR). However, the mechanism was still poorly explored. Herein, our results showed that the level of HO in follicular fluid (FF) and reactive oxygen species (ROS) in GCs were increased, while the expression of SOD1, SOD2 and GPX1 was down-regulated in GCs with DOR. In addition, we found that OS within a certain range promoted the expression of CCL5 in GCs, which facilitated the infiltration of CD8 T cells to the follicles. In vitro co-culture experiment showed that CD8 T cells inhibited GCs proliferation and promoted their apoptosis through intrinsic apoptosis pathway. Maraviroc, the CCR5 antagonist, alleviated CCL5-induced immune attack of CD8 T cells. Our results indicated that ROS-CCL5 axis recruited CD8 T cells into FF resulting in the apoptosis of GCs in DOR. This has further implications for the understanding of the pathology of DOR and searching for the therapeutic management of this disease.