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 2

Tolerogenic MGCA egress from seminiferous tubules of normal mouse testes.

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Tolerogenic MGCA egress from seminiferous tubules of normal mouse testes...
(A) After rabbit anti-LDH3 Ab injection, immune complexes appeared as rabbit IgG puncta (green) outside the occludin+ Sertoli cell barrier (red) in adult WT mouse testes (n = 7) surrounding approximately 18% of seminiferous tubules (B arrows, n = 5), but not in (C) testes of adult Ldh3 null mice (n = 7). (D) No immune complexes were detected in the testes of WT mice injected with rabbit anti-ZAN D3p18 Abs. Original magnification, ×800 (A); ×100 (B); ×800 (C); ×800 (D). Tolerance to LDH3 and ZAN were determined by serum IgG Ab responses to rLDH3 (E and F) or ZAN D3p18 (G) at 3 weeks after immunization with testis homogenate in adjuvant. (E) Comparison of rLDH3 responses between WT male mice (n = 5) and WT female mice (n = 5) and (F) between Ldh3 null male mice (n = 6) and WT male mice (n = 6) are shown. (G) Comparison of ZAN D3p18 responses between WT male mice (n = 5) and WT female mice (n = 3) is shown. Ab responses to (H) rLDH3 and (I) ZAN in WT male mice at 3 weeks after immunization with testis homogenate in adjuvants, with (n = 7) and without (n = 13) concomitant CD25 mAb (PC61) injection are shown. Data in E–I are from 3 independent experiments. *P < 0.05; **P < 0.01, Mann-Whitney U tests.