No abstract

Testes produce spermatozoa that transit through and are stored in the epididymis where they acquire their fertilising capacities. Spermatozoa appear in the genital tract at puberty, long after the immune system was trained to self-antigens. As a consequence, this organ has to set strategies to tolerate sperm antigens to avoid autoimmune responses that would specifically target and destroy them. A recent study pointed the Transforming Growth Factor-beta (TGF-β) signalling in the dendritic cells as a crucial mechanism for epididymal tolerance to spermatozoa. In the mouse, TGF-β exists under three isoforms, and three distinct receptors have been described. Using RT-qPCR, immunohistochemistry and ELISA techniques, we investigated the expression and spatial distribution of the epididymal TGF-β isoforms and of their receptors in young and adult mice. We showed that both ligands and receptors were produced by immune and non-immune cells in the epididymis, whatever the age mice have. These data bring new clues as to the mechanisms of peripheral tolerance to sperm cells in the murine epididymis and raise potential other implications of the cytokine isoforms. After being produced in the testis, spermatozoa transit through and are stored in the epididymis in order to become fully mature. Therefore, the epididymis has a vital role in managing the constant influx of spermatozoa that appear at puberty. The ability to discriminate self-antigens from foreign antigens relies on the tolerance mechanism which encompasses both central and peripheral tolerances. Central tolerance is established before birth or during the perinatal period in mammals, that is long before the production and release of antigens associated with the various stages of sperm development. In this respect, spermatozoa appear as "foreign" to the adult immune system, and are thus managed by peripheral tolerance which is maintained throughout life. This mechanism relies on interactions between antigen-presenting cells and T cells under tolerising conditions, i.e. in the absence of mandatory co-stimulatory signals or in the presence of immunoregulatory cytokines, ligands, leucocyte subsets, or through a combination of these elements 1. These tolerising interactions result in responses ranging from the destruction of antigen-specific T cells to the generation of actively immunosuppressive antigen-specific T cell subsets 1,2. Maintaining peripheral tolerance to sperm cells in the epididymis is crucial for the host to avoid the development of autoimmune reactions such as the production of anti-sperm antibodies (ASAs) which are involved in infertility, by preventing natural sperm/oocyte fusion, and even by interfering with in vitro fertilisation 3-6. Among the well-known tolerising molecules, the transforming growth factor-beta (TGF-β) has proven to be a key cytokine 7. The TGF-β superfamily comprises more than 30 members, including TGF-β isoforms, bone morphogenetic proteins (BMPs), growth and differentiation factors, activins/inhibins, NODAL and the anti-Müllerian h...