Increased NKG2A⁺CD8⁺ T-cell exhaustion in patients with adenomyosis

Immune dysregulation has long been proposed to be associated with adenomyosis, but the underlying mediators and mechanisms remain largely unexplored. Here, we used flow cytometry to investigate the alterations in immune cell subsets in adenomyotic uteri and analyze the phenotype and function of abnormal immune cells. We found that an increase in cluster of differentiation (CD)8⁺ T-cell number was the predominant alteration in ectopic lesions in patients with adenomyosis and was significantly associated with the severity of adenomyosis. Importantly, we identified an exhausted natural killer group protein 2A (NKG2A)⁺CD8⁺ T-cell subset that was associated with the severity of adenomyosis and found that the number of these cells was significantly increased in the eutopic endometrium and ectopic lesions. In addition, the increases in the expression of NKG2A ligand histocompatibility leucocyte antigen E and interleukin-15 in glandular epithelial cells in the adenomyotic microenvironment might contribute to CD8⁺ T-cell exhaustion by promoting NKG2A expression on CD8⁺ T cells or inhibiting the effector function of these cells. In conclusion, our data revealed a previously unrecognized role for NKG2A⁺CD8⁺ T-cell exhaustion in the pathogenesis of adenomyosis, indicating that therapeutic interventions designed to target and reinvigorate exhausted CD8⁺ T cells may be beneficial for patients with adenomyosis.