Immunological dynamics of the epididymis: from experimental insights to clinical translation.

Graphical Abstract: Abstract: The epididymal immune environment is crucial to male fertility as it delicately balances defense against pathogens with tolerance to antigenic spermatozoa. This review synthesizes current knowledge on the epididymal immune landscape under homeostatic and pathological conditions, focusing on the dynamics of resident immune cells and immunomodulatory factors. Distinct immune populations occupy the epididymal epithelium and interstitium, with pronounced regional specialization along the duct. CX3CR1hi intraepithelial mononuclear phagocytes form an extensive surveillance network in the proximal epididymis, supporting epithelial integrity, antigen handling, and controlled immune activation. In the distal regions, heterogeneous interstitial macrophages and conventional dendritic cells coordinate antimicrobial defense and adaptive immune responses. These populations are shaped by a local cytokine milieu enriched in immunomodulatory factors, including TGF-β, activins, and indoleamine 2,3-dioxygenase (IDO), which collectively promote tolerance while restraining inflammation. Regulatory T cells further reinforce cytokine-driven control and prevent antisperm antibody formation. Experimental animal models of epididymitis reveal that disruption of these networks triggers leukocytosis, loss of peripheral tolerance, and tertiary lymphoid structures, sustaining chronic inflammation and autoantibody production, which, in turn, may cause infertility. Both infectious and autoimmune models highlight the cauda epididymis as particularly vulnerable to immune-mediated tissue damage and fibrotic obstruction. Current clinical strategies for the management of epididymitis are reviewed, while postulating possible new therapeutic avenues to target immune and inflammatory pathways that could support existing treatments. In conclusion, this review positions epididymal immune regulation as a central determinant of male fertility and reproductive health while highlighting promising avenues for immunomodulatory interventions to preserve fertility. Lay summary: The epididymis is the organ in which sperm mature and acquire the ability to fertilize an egg. The epididymis has a unique immune system that must protect sperm against infections while avoiding attacks on sperm, which the body recognizes as foreign. This review summarizes how the epididymal immune environment works in both health and disease. Different immune cells populate distinct regions of the epididymis, with specialized roles: some monitor and maintain the tissue, while others combat infections and guide immune responses. Signals from certain molecules help keep the immune system balanced, preventing harmful inflammation or antisperm immune attacks. Studies in animals show that when this balance is disrupted, male fertility can be impaired. Understanding these immune networks could lead to new treatments for diseases such as epididymitis (inflammation of the epididymis), offering ways to protect male fertility by carefully controlling local immune responses.