title: Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy.
abstract: Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae 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.
authors.affiliation: Department of Pathology and Beirne B Carter Center of Immunology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Wheeler
authors.forename: Steve
authors.initials: S
authors.lastname: Tardif
authors.forename: Claudia
authors.initials: C
authors.lastname: Rival
authors.forename: Brian
authors.initials: B
authors.lastname: Luu
authors.forename: Elise
authors.initials: E
authors.lastname: Bui
authors.forename: Roxana
authors.initials: R
authors.lastname: Del Rio
authors.forename: Cory
authors.initials: C
authors.lastname: Teuscher
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Daniel
authors.initials: D
authors.lastname: Hardy
authors.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D004591:Electrophoresis, Polyacrylamide Gel; D007108:Immune Tolerance / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D013094:Spermatozoa / Q000276:immunology*; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014659:Vasectomy
chemical_list: D001323:Autoantibodies; D008565:Membrane Proteins; C096806:zonadhesin