The epididymal immune balance: a key to preserving male fertility

Abstract

Up to 15% of male infertility has an immunological origin, either due to repetitive infections or to autoimmune responses mainly affecting the epididymis, prostate, and testis. Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract. As a consequence, the epididymis, in which posttesticular spermatozoa mature and are stored, has raised some interest in recent years when it comes to its immune mechanisms. Indeed, sperm cells are produced at puberty, long after the establishment of self-tolerance, and they possess unique surface proteins that cannot be recognized as self. These are potential targets of the immune system, with the risk of inducing autoantibodies and consequently male infertility. Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells. These processes rely on incompletely described molecules and cell types. This review compiles recent studies focusing on the immune cell types populating the epididymis, and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response, while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.

Keywords: epididymis; immune response; lymphocytes; mononuclear phagocytes; tolerance.

Figure 1

Model of innate and adaptive responses to urogenital tract ascending pathogens. (a) Epididymal epithelial cells have evolved innate mechanisms that fight pathogens, of which expression of various TLRs, antimicrobial molecules (nitric oxide, IDO, β-defensins, etc.), and pro-inflammatory cytokines (IL-1, IL-6, etc.). (b) In the cauda epididymidis, interstitial B cells may be responsible for the secretion of local IgAs or may phagocytose antibody-coated bacteria and limit their dissemination in the tissue and induce specific effector T cells. Activated B cells may then classically activate helper T cells. (c) In the initial segment, the high proportion of MPs/APCs and canonical effector T cells in the tissue suggest that classical immune responses are set towards pathogens. APCs could sample circulating foreign antigens and present them to effector CD4⁺ and CD8⁺ T cells, inducing cytotoxicity of infected cells while helper T cells sustain the reaction. Depending on the population of APCs, some cells could migrate to the draining lymph node to elicit the recruitment of effector cells to the infected epididymis. (d) In case of epithelial damage due to a severe infection, some CX₃CR1⁺CD11c⁺ MPs may participate in the elimination of cellular or pathogen debris. (e) The newly identified epididymal gd T cells could be activated either by APCs or directly by infected cells. Once activated, they could become cytotoxic thus participating in bacterial clearance. They are also expected to promote epithelial cell maintenance in case of cell injury following severe infections. The epididymal fat pad is suggested as a potential immune reservoir of cytotoxic cells before being recruited during infections. (f) The few monocytes identified in the epididymis are expected to sense local stress signal that induces their extravasation into the tissue and their subsequent differentiation into inflammatory MPs (iDCs and iMΦ) that temporarily sustain the immune response. Ep: epithelium; L: lumen; Int.: interstitium; TJ: tight junction; TLR: Toll-like receptor; NO: nitric oxide; IDO: indoleamine 2,3-dioxygenase; IL: interleukin; Ig: immunoglobulin; Ag: antigen; APC: antigen-presenting cell; MP: mononuclear phagocyte; NK: natural killer cell; NKT: natural killer T cell; iDC: inflammatory dendritic cell; iMf: inflammatory macrophage; Class. mono: classical monocyte; N. class. mono: nonclassical monocyte. Note: parts of the Figure 1–3 use illustrations modified from Servier Medical Art, licensed under the Creative Commons Attribution 3.0 unported license. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ .

Figure 2

Hypothetical complementary mechanisms of early immune surveillance of cancer cells. (a) TGF-β3 has been proposed as an autocrine inhibitor of epididymal epithelial cell growth to limit uncontrolled proliferation. (b) A classical immune response may be set for tumour cells. Modified antigens could be sampled by APCs and presented to effector T cells, inducing a cytotoxic response to epithelial tumour cells. (c) γδ T cells can be directly activated by tumour cells to become cytotoxic and can induce indirect activation of cytotoxic CD8⁺ T cells by upregulating stimulating molecules on the tumour cell surface. γδ T cells can also inhibit angiogenesis. As suggested for the immune response, the epididymal fat pad could participate in the early elimination of cancer cells by the release of such cytotoxic cells as γδ T cells, NK cells and NKT cells. (d) DN T cells can selectively recognize transforming cells and become cytotoxic and suppress them. Ep: epithelium; L: lumen; Int.: interstitium; TJ: tight junction; TGF-β: transforming growth factor-beta; APC: antigen-presenting cell; Ag: antigen; NK: natural killer cell; NKT: natural killer T cell; DNT: double-negative T cell.

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.