Exposed and Sequestered Antigens in Testes and Their Protection by Regulatory T Cell-Dependent Systemic Tolerance

Jessica Harakal, Hui Qiao, Karen Wheeler, Claudia Rival, Alberta G.A. Paul, Daniel M. Hardy, C. Yan Cheng, Erwin Goldberg, Kenneth S.K. Tung*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Continuous exposure of tissue antigen (Ag) to the autoantigen-specific regulatory T cells (Treg) is required to maintain Treg-dependent systemic tolerance. Thus, testis autoantigens, previously considered as sequestered, may not be protected by systemic tolerance. We now document that the complete testis antigen sequestration is not valid. The haploid sperm Ag lactate dehydrogenase 3 (LDH3) is continuously exposed and not sequestered. It enters the residual body (RB) to egress from the seminiferous tubules and interact with circulating antibody (Ab). Some LDH3 also remains inside the sperm cytoplasmic droplets (CD). Treg-depletion in the DEREG mice that express diphtheria toxin receptor on the Foxp3 promoter results in spontaneous experimental autoimmune orchitis (EAO) and Ab to LDH3. Unlike the wild-type male mice, mice deficient in LDH3 (wild-type female or LDH3 NULL males) respond vigorously to LDH3 immunization. However, partial Treg depletion elevated the wild-type male LDH3 responses to the level of normal females. In contrast to LDH3, zonadhesin (ZAN) in the sperm acrosome displays properties of a sequestered Ag. However, when ZAN and other sperm Ag are exposed by vasectomy, they rapidly induce testis Ag-specific tolerance, which is terminated by partial Treg-depletion, leading to bilateral EAO and ZAN Ab response. We conclude that some testis/sperm Ag are normally exposed because of the unique testicular anatomy and physiology. The exposed Ag: 1) maintain normal Treg-dependent systemic tolerance, and 2) are pathogenic and serve as target Ag to initiate EAO. Unexpectedly, the sequestered Ags, normally non-tolerogenic, can orchestrate de novo Treg-dependent, systemic tolerance when exposed in vasectomy.

Original languageEnglish (US)
Article number809247
JournalFrontiers in immunology
StatePublished - May 26 2022


  • Foxp3+ regulatory T cells and systemic tolerance
  • experimental and human autoimmune orchitis
  • exposed and sequestered testis autoantigens
  • post-vasectomy tolerance versus orchitis
  • testis autoantigens and autoantibodies
  • the residual bodies and cytoplasmic droplets

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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