Abstract
The testis is an organ with immune privilege. The comprehensive blood–testis barrier formed by Sertoli cells protects autoimmunogenic spermatozoa and spermatids from attack by the body’s immune system. The interleukin (IL)-6/IL-12 family cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Epstein-Barr virus−induced gene 3 [EBI3]), and IL-35 (p35/EBI3) play critical roles in the regulation of various immune responses, but their roles in testicular immune privilege are not well understood. In the present study, we investigated whether these cytokines are expressed in the testes and whether they function in the testicular immune privilege by using mice deficient in their subunits. Expression of EBI3 was markedly increased at both mRNA and protein levels in the testes of 10- or 12-week-old wild-type mice as compared with levels in 2-week-old mice, whereas the mRNA expression of p40 was markedly decreased and that of p35 was conserved between these two groups. Lack of EBI3, p35, and IL-12 receptor β2 caused enhanced infiltration of lymphocytes into the testicular interstitium, with increased interferon-γ expression in the testes and autoantibody production against mainly acrosomal regions of spermatids. Spermatogenic disturbance was more frequently observed in the seminiferous tubules, especially when surrounded by infiltrating lymphocytes, of these deficient mice than in those of wild-type mice. In particular, p35-deficient mice showed the most severe spermatogenic disturbance. Immunohistochemical analyses revealed that endothelial cells and peritubular cells in the interstitium were highly positive for p35 at both ages, and CD163+ resident macrophages positive for p35 and EBI3, possibly producing IL-35, were also detected in the interstitium of 12-week-old mice but not those of 2-week-old mice. These results suggest that p35 helps in maintaining the testicular immune privilege, in part in an IL-35-dependent manner.
Highlights
Because spermatogenesis begins during puberty, when immune tolerance already has been established, there are various autoimmunogenic materials in the testes that the body’s immune system recognizes as foreign [1]
These results suggest that the mRNA expression of EpsteinBarr virus2induced gene 3 (EBI3) and IL-10 is increased but the mRNA expression of p40 and WSX-1 is markedly decreased in adult testes, implying important roles for IL-35 and IL-10 in adult testes
GATA1 is a maker for Sertoli cells [28], which favor the local immune privilege [29]. These results indicate that endothelial cells and peritubular cells in the interstitium were constitutively positive for p35, and that some CD163+ resident macrophages were positive for EBI3 and p35, possibly producing immunosuppressive IL-35, in addition to Treg cells in the testicular interstitial compartment of adult mice
Summary
Because spermatogenesis begins during puberty, when immune tolerance already has been established, there are various autoimmunogenic materials in the testes that the body’s immune system recognizes as foreign [1]. To protect autoimmunogenic spermatozoa from attack by the immune system, the testes exhibit a distinctive form of immune privilege [1,2,3]. The testicular tissue outside the BTB, where many resident macrophages are normally present, is protected from attack by the body’s immune system [3,5]. To maintain the testicular immune privilege, the testicular cells express and secrete numerous immunoregulatory molecules, including androgens, macrophage migration inhibitory factor, activin, Fas ligand, protein S, and immunosuppressive cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-b, which play critical roles in regulating immune responses in the testes [1,2,3,6]
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