Ag Specific T Effector (TE), Ag specific Foxp3+ regulatory T cells (Treg), and immune complex (IC) interact in a special testicular microenvironment and promote disease progression in a new spontaneous autoimmune orchitis (EAO) model. (83.25)

Abstract BALB/c mice expressing spermatid-specific transgenic ovalbumin (OVA), when crossed to DO11.10 mice, develop spontaneous EAO that begins at 8 wks, which progresses from preclinical stage (8-16 wks) to clinical stage with infertility (>17 wks). Progression time can be reduced to 3 wks by day 3-thymectomy. In preclinical EAO, DC, TE, Treg and OVA-IC are co-localized in, and confined to, discrete non-invasive cell clusters outside the blood-testis barrier (BTB). In clinical EAO, while remaining confined to the clusters, cells become invasive, penetrate the BTB, and deplete germ cells. Why does EAO progress despite persistent expansion and co-localization of activated Ag specific Treg and TE? To address this conundrum, we have accrued the following findings: 1) Changes in the intrinsic TE function: IFNγ-dominance in preclinical EAO versus IL17-dominance in clinical EAO; and adoptively, preclinical T cells transfer preclinical EAO while clinical T cells transfer clinical EAO; 2) only the TE from clinical EAO resist suppression by Treg, 3) In vivo conversion of Treg to Th1 or Th17 TE occurs in testes with clinical EAO; and 4) Infusion of OVA autoAb rapidly results in new IC deposition in the cell clusters, and promotes EAO progression. We conclude that intra-testicular events, within testis cell clusters, critically modify intrinsic properties of both TE and Treg, with the net effect strongly favoring EAO progression. This may depend on activation by co-localized IC.