Regulatory T cells and vasectomy.
CD4+ CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24h of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12-16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at 7 months, the antibody titers fluctuated over time, suggesting a dynamic "balance" between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance.
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Claudia
C
Rival
Karen
K
Wheeler
Sarah
S
Jeffrey
Hui
H
Qiao
Brian
B
Luu
Eric F
EF
Tewalt
Victor H
VH
Engelhard
Stephen
S
Tardif
Daniel
D
Hardy
Roxana
R
del Rio
Cory
C
Teuscher
Kenneth
K
Tung
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism; D004822:Epididymis / Q000473:pathology*; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009920:Orchitis / Q000209:etiology / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014659:Vasectomy / Q000009:adverse effects
C117928:Atrn protein, mouse; D001323:Autoantibodies; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
Autoimmune orchitis; Genetic control of autoimmunity; Post-vasectomy sequel; Regulatory T cells; Sperm autoantibodies; Tolerance