Expression of transgenic FLIP on thyroid epithelial cells in CBA/J mice inhibits induction and promotes resolution of granulomatous experimental autoimmune thyroiditis (G-EAT) (129.17)

Abstract

Abstract G-EAT is induced by transfer of thyroglobulin-primed in vitro activated splenocytes. In EAT susceptible DBA/1 and CBA/J mice, inflammation either resolves or progresses to fibrosis by day 60 depending on the extent of damage at day 20. Depletion of CD8+ T cells inhibits G-EAT resolution. We previously showed that FLIP transgene (Tg) expressed on thyroid epithelial cells (TEC) of DBA/1 mice had no effect on induction, but promoted earlier resolution of G-EAT. However, when Tg+ CBA/J mice expressing FLIP on TEC were used as recipients of WT donor splenocytes, they developed less severe G-EAT than FLIP Tg− littermates (average severity score of 1.3 vs. 4.5 at day 20), although both strains had similar levels of FLIP transgene. Following transient depletion of CD8+ T cells, FLIP Tg+ and Tg− CBA/J recipients both developed severe G-EAT (severity score of 4.4) at day 20. Lesions in CD8-depleted Tg+ recipients were resolving by day 60, whereas lesions in Tg− littermates did not resolve and most were fibrotic. FLIP and FasL were mainly expressed by TEC in FLIP Tg+ recipients and by inflammatory cells in Tg− recipients. mRNA expression of IL-10 and IL-13 was higher, and IFN-γ and TNF-α were lower, in FLIP Tg+ compared to Tg− recipients. The results support the hypothesis that transgenic FLIP expressed on TEC in CBA/J mice promotes G-EAT resolution, but induction of G-EAT is inhibited unless CD8+ T cells are depleted (NIH Grant DK35527).