Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance
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
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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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 1

Testis anatomy and selective MGCA sequestration.

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Testis anatomy and selective MGCA sequestration. (A) Sperm production oc...
(A) Sperm production occurs in cycles (different colors) longitudinally along seminiferous tubules (SFT) (ia, ib). Mature sperm are transported to the vas deferens (v) via the rete testis (ii), ductus efferentes (iii), and epididymis (iv). (B) Seminiferous tubules, visualized by IF on Scx-GFP mouse testes with GFP+ Sertoli cells (green) and LDH3 (red), contain LDH3– spermatogonia (white arrows) and LDH3+ spermatocytes (yellow arrows). Insert: occludin+ Sertoli cell barriers (red) located between adjacent Sertoli cells (green). I/T, interstitial space. Original magnification, ×500; ×800 (insert). (C) A seminiferous tubule segment with 2 Sertoli cells (light green) depicts the complete MGCA sequestration paradigm. Sertoli cells support spermatogenesis (steps i–iv) and spermiation (steps v–ix). Spermatogonia (i) traverse the Sertoli cell barriers to become MGCA+ spermatocytes (ii, pink), then round (iii) and elongating (iv) spermatids. At spermiation, redundant cytoplasm (yellow) and plasma membrane (black) are partially detached from elongated spermatids (v) to form residual bodies (vi) destined for degradation inside Sertoli cells (vii), and retained as cytoplasmic droplets (viii) on mature sperm (ix). The interstitial space contains spermatogonia, basal lamina, peritubular cells (not shown), Leydig cells, macrophages, and afferent lymphatic vessels (not shown). Sertoli cells and Sertoli cell barriers (purple) sequester all MGCA+ meiotic germ cells inside seminiferous tubules. (D) The new selective MGCA sequestration paradigm supported by our study is shown. Tolerogenic NS-MGCA are located in residual bodies and not removed by Sertoli cells. They enter the basal Sertoli cell cytoplasm and egress into the interstitial space. S-MGCA, including those in the sperm acrosome (green crescent), absent from residual bodies, are nontolerogenic. Note that some, but not all, residual bodies are destroyed by the Sertoli cells (vii).