Figure 3: Model of immune tolerance to sperm cells at steady state or following an interstitial leak of sperm antigens. (a–c) The epididymal epithelial cells are known to express several molecules implicated in the inhibition of activation ([a] IL-10, activin A, [c] TGF-β) or in the killing of activated T cells ([b]IDO). This list may not be exhaustive. (d) In particular cases such as severe tissue injuries leading to a leak of sperm antigens into the interstitium, tissue CD103+ DCs may migrate to the draining lymph node where they present some MGCAs to T cells. The activation of lymph node T cells could then lead to the epididymal recruitment of Treg cells able to inhibit effector T cells activation thanks to their secretion of IL-10 and TGF-β. (e) A classical way to induce a tolerogenic response is the weak activation of effector cells by local APCs in an immunosuppressive microenvironment, leading either to their anergy or to their apoptosis. (f) A new immunosuppressive population of DN T cells has been described in the mouse epididymis. As in other organs, they are proposed to become activated by local APCs and become cytotoxic to activated T cells and APCs. Ep: epithelium; L: lumen; Int.: interstitium; TJ: tight junction; IL: interleukin; TGF-β: transforming growth factor-beta; IDO: indoleamine 2,3-dioxygenase; APC: antigen-presenting cell; Ag: antigen; DN T: double negative T cell; Treg: regulatory T cell; DC: dendritic cell; MGCAs: meiotic germ cell antigens.