Maia Lina Elizagaray, Ferran Barrachina, Maria C. Avenatti, Isinsu Bastepe, A. Chen, Ainize Odriozola, Oluchi Ukairo, Vanina G. Da Ros, Kiera Ottino, Nerea Subirán, María Agustina Battistone
Gaps in knowledge about the epididymal mucosa contribute to the prevalent classification of male idiopathic infertility. Inflammatory triggers, such as infections and autoimmunity, can breach immune privilege, induce anti-sperm antibody (ASA) production, and impair fertility. However, the mechanisms governing ASA production are poorly characterized. Here, using a murine model of epididymitis induced by regulatory T cell (Treg) depletion, we show that the disruption of immunotolerance leads to chronic autoimmunity characterized by the presence of ASA, and distinct testicular and epididymal immune landscapes. These inflammatory features impair sperm function, contribute to epididymal damage, and drive subfertility. Treg depletion induces the formation of tertiary lymphoid structures (TLS) within the epididymis, as indicated by the presence of B and T cell clusters, fibroblasts, and high endothelial venules. Similar autoantibody responses were detected in the seminal plasma of infertile patients, suggesting conserved mechanisms. Thus, we provide an in-depth analysis of immune cell dynamics and TLS during epididymitis, offering insights for the development of precision-targeted therapies for fertility disorders, as well as the identification of new contraceptive strategies. Chronic inflammation affects the male reproductive system, contributing to infertility. Using a mouse model of epididymitis, here, the authors report on the formation of tertiary lymphoid structures (TLS) under conditions of chronic inflammation, and show that TLSs sustain immune activation, contributing to anti-sperm autoantibody production and epididymal injury.