Persistence of physiological self antigen is required for the regulation of self tolerance

Endogenous Ag requirement for induction and maintenance of T cell tolerance has been extensively investigated in mice that express a transgenic Ag and /or its cognate transgenic TCR, In contrast, studies on tolerance for physi ologically expressed self Ag and normal T cells are limited. Herein, we sho wed that the murine ovarian-specific ZP3 Ag is detectable from birth. Toler ance to ZP3 is detected in female relative to male mice. In comparison to m ales, 100-fold more ovarian peptide (pZP3) is required to elicit a comparab le pathogenic response in females, Female tolerance to pZP3 was dependent o n the presence of endogenous ovarian Ag, because neonatal ovariectomy conve rted the female response to that of males. Moreover, in female mice that we re ovariectomized from the ages of 1-6 wk, the pZP3 responses were enhanced to the male level if ovaries were removed up to 7 days, but not 3 days, be fore adult challenge with pZP3. Thus, the physiologically expressed ZP3 Ag induces tolerance to pZP3, and the maintenance of tolerance is critically d ependent on the continuous presence of the endogenous ovarian Ag, In contra st, exposure to endogenous ovarian Ag confined to the neonatal period is in sufficient for the induction and maintenance of tolerance to ZP3.