Impact of Functional Diversity in Epididymal Epithelial and Immune Cells on Male Fertility

Battistone Maria Agustina

Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital

Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, MA, United States

Abstract Text:

One of the most intriguing aspects of male reproductive physiology is the epididymis's unique ability to prevent immune responses against foreign antigens carried by spermatozoa and initiate robust immune responses against stressors. Epithelial clear cells (CCs), strategically positioned in the epididymis, collaborate with region-specific subsets of mononuclear phagocytes (MPs) to maintain the delicate balance between immune tolerance and inflammation in the post-testicular environment. Our lab has identified unexpected roles for CCs, including the transfer of novel proteins to sperm via extracellular vesicles and nanotubes during their transit along the epididymal tubule. We have also characterized the immune phenotype, morphology, and antigen-capturing, processing, and presenting capabilities of epididymal MPs. We described a comprehensive analysis of CC-MP communication networks in steady-state and injury conditions. Our findings revealed distinct region-specific humoral and cellular immune responses during LPS-induced epididymitis, which negatively impact the organ and contribute to male fertility disorders. Moreover, in an autoimmune epididymitis model induced by regulatory T cell (Treg) depletion, we observed the formation of tertiary lymphoid structures (TLSs) in the distal epididymis. These TLSs act as central hubs for local autoantibody production and chronic inflammation, both of which play a critical role in the development of fertility issues. Ultimately, our study offers new perspectives on the largely unexplored immune dynamics within the epididymis, advancing our understanding of mucosal immunity and the critical cell-cell interactions that are vital for male reproductive health.