Expression of transgenic FLIP on thyroid epithelial cells inhibits induction and promotes resolution of granulomatous experimental autoimmune thyroiditis in CBA/J mice.
Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by transfer of thyroglobulin-primed in vitro activated splenocytes. Thyroid lesions reach maximal severity 20 d later, and inflammation resolves or progresses to fibrosis by d 60, depending on the extent of thyroid damage at d 20. Depletion of CD8+ T cells inhibits G-EAT resolution. We showed that expression of Fas-associated death domain-like IL-1beta-converting enzyme inhibitory protein (FLIP) transgene (Tg) on thyroid epithelial cells (TECs) of DBA/1 mice had no effect on G-EAT induction but promoted earlier resolution of G-EAT. However, when CBA/J wild-type donor cells were transferred to transgenic CBA/J mice expressing FLIP on TECs, they developed less severe G-EAT than FLIP Tg- littermates. Both strains expressed similar levels of the FLIP Tg, but endogenous FLIP was up-regulated to a greater extent on infiltrating T cells during G-EAT development in DBA/1 compared with CBA/J mice. After transient depletion of CD8+ T cells, FLIP Tg+ and Tg- CBA/J recipients both developed severe G-EAT at d 20. Thyroid lesions in CD8-depleted Tg+ recipients were resolving by d 60, whereas lesions in Tg- littermates did not resolve, and most were fibrotic. FLIP Tg+ recipients had increased apoptosis of CD3+ T cells compared with Tg- recipients. The results indicate that transgenic FLIP expressed on TECs in CBA/J mice promotes G-EAT resolution, but induction of G-EAT is inhibited unless CD8+ T cells are transiently depleted.
Fang
Yujiang
Y
Division of Immunology and Rheumatology, Department of Medicine, University of Missouri, NE307 Medical Sciences, Columbia, MO 65212, USA.
DeMarco
Vincent G
VG
Sharp
Gordon C
GC
Braley-Mullen
Helen
H
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013961:Thyroid Gland / Q000166:cytology; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013968:Thyroiditis, Subacute / Q000235:genetics / Q000276:immunology* / Q000378:metabolism