title: 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.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
authors.forename: Jessica
authors.initials: J
authors.lastname: Harakal
authors.forename: Hui
authors.initials: H
authors.lastname: Qiao
authors.forename: Claudia
authors.initials: C
authors.lastname: Rival
authors.forename: Jonathan C H
authors.initials: JC
authors.lastname: Li
authors.forename: Alberta G A
authors.initials: AG
authors.lastname: Paul
authors.forename: Karen
authors.initials: K
authors.lastname: Wheeler
authors.forename: Patcharin
authors.initials: P
authors.lastname: Pramoonjago
authors.forename: Constance M
authors.initials: CM
authors.lastname: Grafer
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sampson
authors.forename: Elissa W P
authors.initials: EW
authors.lastname: Wong
authors.forename: Prabhakara P
authors.initials: PP
authors.lastname: Reddi
authors.forename: Umesh S
authors.initials: US
authors.lastname: Deshmukh
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hardy
authors.forename: Huanghui
authors.initials: H
authors.lastname: Tang
authors.forename: C Yan
authors.initials: CY
authors.lastname: Cheng
authors.forename: Erwin
authors.initials: E
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012671:Seminiferous Tubules / Q000276:immunology*; D012708:Sertoli Cells / Q000276:immunology; D013091:Spermatogenesis / Q000276:immunology*; D013094:Spermatozoa / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001324:Autoantigens