Fas/Fas ligand-driven T cell apoptosis as a consequence of ineffective thyroid immunoprivilege in Hashimoto's thyroiditis

Hashimoto's thyroiditis (HT) is a chronic autoimmune disease resulting from Fas-mediated thyrocyte destruction. Although autocrine/paracrine Fas-Fas l igand (FasL) interaction is responsible for thyrocyte cell death during the active phases of HT, the role of infiltrating T lymphocytes (ITL) in this process is still unknown. Therefore, we investigated the expression and fun ction of Fas and Fast in ITL, All ITL expressed high levels of Fas and CD69 , an early marker of T cell activation associated with functional Fas expre ssion in T cells in vivo. In contrast to thyrocytes that were found to prod uce high levels of Fast, ITL did not express significant amounts of FasL, s uggesting that ITL are not directly involved in thyrocyte destruction. The analysis of ITL purified from HT thyroids showed that ITL were massively ki lled by Fas crosslinking and that a considerable number (24-36%) underwent spontaneous apoptosis within 36 h of culture. Accordingly, in situ TUNEL (t erminal deoxynucleotidyl transferase dUTP nick end labeling) staining revea led that a significant number (10-15%) of ITL in proximity to Fast-producin g thyroid follicles were apoptotic, Moreover, virtually all ITL in proximit y to thyroid follicles were preapoptotic, as they expressed high levels of GD3 ganglioside, a killer glycolipid responsible for the generation of irre versible apoptotic signals that accumulate in hematopoietic cells shortly a fter Fas crosslinking, These data demonstrate that ITL are not directly inv olved in thyrocyte cell death during HT, suggesting that autocrine/paracrin e Fas-FasL interaction is a major mechanism in autoimmune thyrocyte destruc tion.