Natural Regulatory T Cell Controls Physiological Tolerance And Regional Immune Privilege: Studies on (C57BL/6xA/J) F1 (B6AF1) DEREG (“depletion of regulatory T cell”) Mice (171.9)

Abstract

Abstract Although CD4+CD25+ Foxp3+ regulatory T cell (Treg) prevents autoimmune disease, its depletion in normal mice does not cause organ-specific autoimmunity, thus Treg’s physiological role in tolerance remains unclear. Different outcomes after Treg depletion in two models of Diphtheria toxin (DT) receptor-Foxp3 adult B6 mice have been reported: scurfy syndrome versus no effect. Herein, we report autoimmune disease of testis, ovary, stomach and lacrimal gland in the DEREG B6AF1 mice after Treg depletion. Male B6AF1 DEREG mice show massive immune complex and complement deposition, defective blood-testis barrier, and loss of sperm production. Importantly, immune injury is preceded by defective testis immune privilege, which also occurs reversibly in B6 DEREG mice that lack testis-specific autoAb. AutoAb in male B6AF1 DEREG mice target germ cells but also antigen common to steroidogenic testis (Leydig) cells and ovarian cells. In fact, male CD4 T cells adoptively transfer both orchitis and oophoritis; and autoAb of female B6AF1 DEREG mice with oophoritis targets a different ovarian Ag: the zona pellucida. These findings indicate gender-specific tolerance mechanisms. Notably, the Abs and gonadal failure are part of the human autoimmune polyendocrine syndrome (APS), some with autoimmune regulator (AIRE) gene mutations. Therefore, natural Treg control physiological systemic and regional tolerance to major gonadal Ag and Treg deficiency could explain APS and AIRE-related autoimmunity.