The testis in immune privilege

The production, differentiation, and presence of male gametes represent inimitable challenges to the immune system, as they are unique to the body and appear long after the maturation of the immune system and formation of systemic self-tolerance. Known to protect germ cells and foreign tissue grafts from autoimmune attack, the 'immune privilege' of the testis was originally, and somewhat simplistically, attributed to the existence of the blood-testis barrier. Recent research has shown a previously unknown level of complexity with a multitude of factors, both physical and immunological, necessary for the establishment and maintenance of the immunotolerance in the testis. Besides the blood-testis barrier and a diminished capability of the large testicular resident macrophage population to mount an inflammatory response, it is the constitutive expression of anti-inflammatory cytokines in the testis by immune and particularly somatic cells, that represents an essential element for local immunosuppression. The role of androgens in testicular immune regulation has long been underestimated; yet, accumulating evidence now shows that they orchestrate the inhibition of proinflammatory cytokine expression and shift cytokine balance toward a tolerogenic environment. Furthermore, the role of the testicular dendritic cells in suppressing antigen-specific immunity and T-lymphocyte activation is discussed. Finally, the active role mast cells play in the induction and amplification of immune responses, both in infertile humans and in experimental models, highlights the importance of preventing mast cell activation to maintain the immune-privileged status of the testis.