Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege.
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.
Department of Anatomy, Tokyo Medical University, Tokyo, Japan; Department of Anatomy, Tokai University School of Medicine, Kanagawa, Japan.
Hayato
H
Terayama
Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Takayuki
T
Yoshimoto
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Shuichi
S
Hirai
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Munekazu
M
Naito
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Ning
N
Qu
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Naoyuki
N
Hatayama
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Shogo
S
Hayashi
Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Kana
K
Mitobe
Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Jun-Ichi
J
Furusawa
Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Izuru
I
Mizoguchi
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Takeshi
T
Kezuka
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.
Hiroshi
H
Goto
Department of Anatomy, Tokai University School of Medicine, Kanagawa, Japan.
Kaori
K
Suyama
Department of Anatomy, Showa University School of Medicine, Tokyo, Japan.
Hiroshi
H
Moriyama
Department of Anatomy, Tokai University School of Medicine, Kanagawa, Japan.
Kou
K
Sakabe
Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
Masahiro
M
Itoh
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001814:Blood-Testis Barrier / Q000276:immunology*; D042783:Endothelial Cells / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D012671:Seminiferous Tubules / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000254:growth & development / Q000276:immunology*
D001323:Autoantibodies; C499601:Ebi3 protein, mouse; D053765:Interleukin-12 Subunit p35; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; C569375:interleukin-35, mouse