Contributions of T-helper 9 cells in endometriosis-associated inflammation and lesion growth.

Endometriosis is an inflammatory gynecologic disease characterized by ectopic growth of endometrial-like tissue, resulting in pelvic pain and infertility. T-helper 9 (Th9) cells play a known role in various chronic inflammatory diseases. Despite parallels between endometriosis and Th9-driven diseases, their role in endometriosis has not been extensively explored. We investigated Th9 cell involvement in endometriosis pathophysiology using human tissue samples, in vitro experiments with human-derived Th9 cells, and in vivo experiments to shed insight on the impact of adoptively transferred Th9 cells in our established syngeneic endometriosis mouse model. Immunohistochemistry of a tissue microarray revealed significantly increased IL-9-positive cells in patient lesions compared to control endometrium. Human CD4+ Th cells purified from peripheral blood mononuclear cells treated with Th9-driving growth factors produced significantly altered proinflammatory mediators (increased IL-5 and IL-17F; decreased IL-8) in response to estrogen stimulation. Adoptive transfer of mouse Th9-like cells increased plasma IL-1α concentration and altered transcriptional profiles of several signaling pathways, including Notch and PI3K-Akt. Immunofluorescent microscopy depicted adoptively transferred Th9 cells present within mouse lesions. Furthermore, immunohistochemical analysis demonstrated reduced lesion proliferation following Th9 adoptive transfer. This study provides the first evidence that Th9 cells likely promote immune-inflammatory alterations within lesions to exacerbate disease.