Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy

Karen Wheeler, Steve Tardif, Claudia Rival, Brian Luu, Elise Bui, Roxana Del Rio, Cory Teuscher, Tim Sparwasser, Daniel Hardy, Kenneth S.K. Tung

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand thelong-termsequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4+CD25 +Foxp3+ regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function - a possible genetic trait - can influence the divergent tolerogenic versus autoimmune response to vasectomy.

Original languageEnglish (US)
Pages (from-to)7511-7516
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number18
DOIs
StatePublished - May 3 2011
Externally publishedYes

Keywords

  • Granulomatous inflammation
  • Innate response
  • Testis autoantigen
  • Vasoligation

ASJC Scopus subject areas

  • General

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