Natural regulatory T cells (Treg) determine post vasectomy sequlae: autoimmune orchitis (EAO) versus testis-specific tolerance.

Abstract Vasectomy (Vx), a popular male contraceptive, causes a persistent epididymal granuloma. Using unilateral Vx (uni-Vx) as an inducer of a localized danger signal, we queried whether Treg control the transition to autoimmunity. When Treg were depleted (CD25 Ab) in uni-Vx mice, frequent and bilateral EAO developed. This was accompanied by T cell activation in the regional lymph node and a robust testis antibody response. CD4+ T cells that produced IFNγ predominated in the diseased testes. CD4+ T cells are sufficient for disease induction as in vivo depletion of CD4+ cells blocked the emergence of EAO and CD4+ cells from uni-Vx mice were able to adoptively transfer disease. We also identified sperm Zonadhesin (Zan) as the major orchitogenic autoantigen. By immunoblot, autoantibodies from uni-Vx mice prominently recognized Zan, and immunization with Zan in adjuvant induced EAO. As EAO induction in Vx men would be devastating, we depleted Treg two weeks following uni-Vx and found they were free of EAO. To test whether uni-Vx in fact induces tolerance to testicular antigens, we compared uni-Vx and Sham-Vx mice in their response to EAO induction by immunization with testis homogenate in CFA. Indeed, uni-Vx mice developed significantly lower EAO scores and autoantibody and T cell proliferative responses. Thus, Treg protect Vx mice from post-Vx EAO by blocking propagation of danger signals to pathogenic autoimmunity while granting systemic tolerance to testis antigens.