Tung Kenneth S K, Harakal Jessica, Qiao Hui, Rival Claudia, Li Jonathan C H, Paul Alberta G A, Wheeler Karen, Pramoonjago Patcharin, Grafer Constance M, Sun Wei, Sampson Robert D, Wong Elissa W P, Reddi Prabhakara P, Deshmukh Umesh S, Hardy Daniel M, Tang Huanghui, Cheng C Yan, Goldberg Erwin
J Clin Invest. 2017 Mar 1;127(3):1046-1060. doi: 10.1172/JCI89927. Epub 2017 Feb 20.
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.
在人类不育症患者以及输精管结扎术后，会出现针对精子和睾丸上表达的减数分裂生殖细胞抗原（MGCA）的自身免疫反应。许多MGCA在人类癌症中也作为癌胚抗原（CTA）表达，但MGCA的耐受状态尚未得到研究。MGCA被认为具有一致的免疫原性且无耐受性，普遍观点认为MGCA被隔离在生精小管的支持细胞屏障之后。在此，我们已经表明只有一些小鼠MGCA被隔离。未被隔离的MCGA（NS-MGCA）从正常小管中逸出，这可通过它们与全身注射的抗体相互作用并在支持细胞屏障外形成局部免疫复合物的能力得到证明。NS-MGCA源自精子形成过程中精子细胞丢弃的细胞碎片。它们作为残余小体中的货物逸出并维持依赖调节性T细胞的生理耐受性。相比之下，隔离的MGCA（S-MGCA）在残余小体中无法检测到且无耐受性。与输精管结扎术后的自身抗体主要靶向S-MGCA不同，正常小鼠在短暂的调节性T细胞耗竭后发生自身免疫性睾丸炎所产生的自身抗体仅靶向NS-MGCA。我们得出结论，精子形成作为精子发生过程中的一个生理检查点，决定了MGCA的逸出和耐受性。我们的发现将影响睾丸和精子自身免疫中的靶抗原选择以及男性癌症患者对CTA的免疫反应。
