Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance
Kenneth S.K. Tung, … , C. Yan Cheng, Erwin Goldberg
Kenneth S.K. Tung, … , C. Yan Cheng, Erwin Goldberg
Published February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):1046-1060. https://doi.org/10.1172/JCI89927.
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Research Article Immunology Reproductive biology

Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance

Abstract

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.

Authors

Kenneth S.K. Tung, Jessica Harakal, Hui Qiao, Claudia Rival, Jonathan C.H. Li, Alberta G.A. Paul, Karen Wheeler, Patcharin Pramoonjago, Constance M. Grafer, Wei Sun, Robert D. Sampson, Elissa W.P. Wong, Prabhakara P. Reddi, Umesh S. Deshmukh, Daniel M. Hardy, Huanghui Tang, C. Yan Cheng, Erwin Goldberg

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Figure 6

Stage-specific OVA localization and detection in residual bodies of OVA-Hi mice.

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Stage-specific OVA localization and detection in residual bodies of OVA-...
(A) IP staining in a longitudinal seminiferous tubule section of an OVA-Hi mouse testis. Note: OVA+ residual bodies (arrows) are with sperm at stage VIII, but are randomly distributed throughout the seminiferous tubule at stage IX. (B) OVA+ residual bodies with high OVA content are maximally detected at stage IX of the spermatogenic cycle (significance between stage IX and all other stages ranges from significant to highly significant). *P < 0.05; **P < 0.01; ***P < 0.001, Kruskal-Wallis test. (C) Residual bodies (indicated by arrows) in OVA-Hi mouse testis at stage IX: OVA (green) is enclosed by membrane-associated tACE, a residual body marker (red). (D) Most OVA+ residual bodies (red) in OVA-Hi × Scx-GFP F1 testis at stage IX do not costain with Sertoli cell cytoplasm (green), including the very small residual bodies at the base of seminiferous tubules (yellow rectangle). Some OVA is inside the Sertoli cell cytoplasm (yellow) with plexiform distribution (white square). (E) Diffuse OVA IP staining confined to the basal cytoplasm of Sertoli cells in OVA-Hi mouse testis at stage IX (arrow). (F) OVA+ puncta (red) are inside the basal Sertoli cell cytoplasm (yellow, arrows) in OVA-Hi × Scx-GFP F1 mouse testis at stage IX. (G) Small OVA+ speckles detected by IP staining in the interstitial space of OVA-Hi mouse testes (arrows) at stage VIII (left) and stage IX (right). All images are representative of 3–4 experiments. Dotted white lines denote the boundary of seminiferous tubules. Original magnification, ×100 (A); ×400 (C–F); ×800 (G).