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

Area of Science:

• Immunology
• Reproductive Biology
• Autoimmunity

Background:

• Systemic tolerance relies on continuous antigen exposure to regulatory T cells (Treg).
• Testis autoantigens were historically considered sequestered, implying protection from immune surveillance.
• The unique anatomy and physiology of the testes may lead to unexpected antigen exposure.

Purpose of the Study:

• To investigate the exposure status of testis/sperm antigens and their role in immune tolerance and autoimmunity.
• To determine if exposed antigens maintain tolerance or can initiate autoimmune orchitis (EAO).
• To explore the immunogenicity of sequestered antigens when experimentally exposed.

Main Methods:

• Utilized DEREG mice with diphtheria toxin receptor on Foxp3 promoter for Treg depletion.
• Investigated immune responses to lactate dehydrogenase 3 (LDH3) and zonadhesin (ZAN) in wild-type and antigen-deficient mice.
• Examined the effects of vasectomy on immune tolerance to sperm antigens.

Main Results:

• Lactate dehydrogenase 3 (LDH3), a sperm antigen, is continuously exposed and not sequestered.
• Treg depletion in DEREG mice induced experimental autoimmune orchitis (EAO) and antibodies to LDH3.
• Mice lacking LDH3 responded vigorously to immunization, and partial Treg depletion increased responses in wild-type males.
• Exposed zonadhesin (ZAN) and other sperm antigens after vasectomy rapidly induced tolerance, which was lost upon Treg depletion, leading to EAO.

Conclusions:

• Some testis/sperm antigens are normally exposed, maintaining Treg-dependent systemic tolerance and acting as targets in EAO.
• Exposed antigens can be pathogenic, initiating autoimmune responses when tolerance mechanisms are compromised.
• Sequestered antigens, upon experimental exposure (e.g., vasectomy), can induce de novo Treg-dependent systemic tolerance.