Interleukin-35 plays a pivotal role in maintaining the testicular immune            privilege

Terayama Hayato, Yoshimoto Takayuki, Naito Munekazu, Hirai Shuichi, Qu Ning, Hatayama Naoyuki, Hayashi Shogo, Kanazawa Teruhisa, Suyama Kaori, Sakabe Kou, Itoh Masahiro

doi:10.3192/jsirib.29.13

Background: Testis is known as one of the immunologically privileged organs. In particular, blood-testis barrier formed by Sertoli cells protects autoimmunogeneic spermatozoa and spermatid from attack by the self-immune system. Moreover, it was demonstrated that Sertoli cells, Leydig cells and a few population of testicular macrophages exhibit immunosuppressive activity. Recent studies also suggest a possibility that some cytokines in the testis contribute to maintaining the immune privilege. Interleukin (IL)-35 is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12. Although it is IL-35 has an important role in immunosuppression, its role in the testis remains unknown. Methods and Findings: In the present study, we investigated the role of intra-testicular IL-35 by histochemistry, immunohistochemistry and real-time RT-PCR using wild-type C57BL/6 mice and EBI3- and p35-deficient mice. EBI3 expression was detected in a part of CD163-positive macrophages and acrosomal regions of spermatids in testis of wild-type mice. Intriguingly, p35 expression was coincidently detected in a part of EBI3- and F4/80-positive macrophages, and also in basal lamina of seminiferous tubules, endothelial cells and acrosomal region of spermatids. A significant increase in the number of seminiferous tubules with spermatogenic disturbance was observed in both EBI3- and p35-deficient mice, compared with that in wild-type mice. Especially, p35-deficient mice showed severe spermatogenic disturbance. Moreover, CD4-, CD8- and B220-positive infiltrating cells were detected in the testicular interstitium of EBI3- and p35-deficient mice, but not of wild-type mice. Intra-testicular mRNA expression of interferon-gamma was significantly increased in EBI3- and p35-deficient mice. A similar increase in the expression of IL-10 was observed only in p35-deficient mice. Finally, autoantibodies to spermatids were detected in sera obtained from EBI3- and p35-deficient mice, but not from wild-type mice. Conclusions: In testis, there are EBI3- and p35-double positive macrophages, possibly producing immunosuppressive IL-35. And, lack of either EBI3 or p35 causes infiltration of lymphocytes into testis and spermtatogenic disturbance. These results indicate that IL-35 plays an important role in maintaining the testicular immune privilege.

Interleukin-35 plays a pivotal role in maintaining the testicular immune privilege

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