Identification of proliferating CD103+ CD8+ tissue-resident memory-like T-cells in villitis of unknown etiology in human placenta.

Abstract

Villitis of unknown etiology (VUE) is a destructive inflammatory lesion of unknown cause in the human placenta. It may be caused by semiallogeneic rejection of fetal tissue by the mother. CD8⁺ tissue-resident memory T (T_RM) cells reside in the peripheral tissues and have an important role in the local defense against reinfection. These cells also contribute to immunopathogenesis under some circumstances and cause local tissue damage and autoimmune disease. In this study, we examine the contribution of CD103⁺ CD8⁺ T_RM-like cells to the development of VUE. The study included 23 cases of human placenta diagnosed as VUE (high-grade). Double-labeling immunohistochemistry was performed in formalin-fixed paraffin-embedded tissues. CD103⁺ CD8⁺ cell accumulation in actively inflamed areas was observed in all cases. The double positivity rate for CD103 and CD8 among the total CD103⁺ and CD8⁺ cells was 95% (71-100%) and 58% (18-90%) [median (range)], respectively. This indicated that the vast majority of CD103⁺ cells in VUE are CD103⁺ CD8⁺ T_RM-like cells. CD103⁺ cells exhibited a significantly high proliferative activity based on a Ki-67 labeling index in CD103⁺ cells of 52% (13-90%). CD103⁺ cells were aligned beneath E-cadherin⁺ syncytiotrophoblast cells (subtrophoblast alignment) in the peripheral areas of the VUE lesions. Syncytiotrophoblast cells in VUE were also characterized by the induction of human leukocyte antigens A, B, and C expression. CD103⁺ cells also expressed granzyme B. Our results suggest that proliferating CD103⁺ CD8⁺ T_RM-like cells work as cytotoxic effector cells and play an important role in VUE pathogenesis.