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Regulatory T cells and vasectomy.

Claudia Rival1, Karen Wheeler, Sarah Jeffrey

  • 1Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.

Journal of Reproductive Immunology
|October 2, 2013
PubMed
Summary

Vasectomy induces immune tolerance to meiotic germ cell antigens (MGCA) through regulatory T cells (Tregs). Delayed Treg depletion prevents this tolerance, highlighting the critical role of early immune responses in preventing autoimmune orchitis.

Keywords:
Autoimmune orchitisGenetic control of autoimmunityPost-vasectomy sequelRegulatory T cellsSperm autoantibodiesTolerance

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Area of Science:

  • Immunology
  • Reproductive Biology
  • Autoimmunity

Background:

  • CD4+ CD25+ regulatory T cells (Tregs) significantly impact autoimmune responses to meiotic germ cell antigens (MGCA) and gonadal immunopathology.
  • Unilateral vasectomy (uni-vx) in mice triggers rapid epididymal inflammation, apoptosis, and granuloma formation.
  • Vasectomy unexpectedly induces MGCA-specific tolerance, but simultaneous Treg depletion leads to autoimmune orchitis.

Purpose of the Study:

  • To investigate the role of Tregs in the development of autoimmune responses and tolerance following vasectomy.
  • To determine the temporal relationship between epididymal injury, Treg activity, and the onset of autoimmunity or tolerance.
  • To explore the long-term stability of vasectomy-induced tolerance and its clinical implications.

Main Methods:

  • Unilateral vasectomy (uni-vx) was performed on mice.
  • Regulatory T cell (Treg) depletion was induced simultaneously or with a delayed timing.
  • Immune responses to meiotic germ cell antigens (MGCA), including autoimmune orchitis and antibody production, were assessed.
  • Mice deficient in PD-1 ligand were used to investigate the role of induced Tregs.

Main Results:

  • Vasectomy alone induced MGCA-specific tolerance, while simultaneous Treg depletion resulted in autoimmune orchitis.
  • Delayed Treg depletion (one week post-vasectomy) prevented tolerance induction, indicating tolerance depends on a rapid de novo Treg response.
  • Tolerance was impaired in mice deficient in PD-1 ligand, suggesting the involvement of induced Tregs.
  • Vasectomized mice remained resistant to autoimmune orchitis for 12-16 months, indicating long-lasting tolerance.
  • Low titers of sperm autoantibodies were detected but fluctuated, suggesting a dynamic balance between autoimmunity and tolerance.
  • Severe epididymal fibrosis and hypo-spermatogenesis were observed 12 months post-vasectomy.

Conclusions:

  • Pre-existing natural Tregs prevent post-vasectomy autoimmunity, while vasectomy-induced Tregs maintain long-lasting tolerance.
  • The timing of Treg response relative to epididymal injury is critical for establishing tolerance or autoimmunity.
  • Vasectomy leads to long-term immune tolerance but results in significant long-term gonadal pathology, highlighting critical clinical concerns.