THYROTROPIN-RECEPTOR AND THYROID PEROXIDASE-SPECIFIC T-CELL CLONES AND THEIR CYTOKINE PROFILE IN AUTOIMMUNE THYROID-DISEASE

We studied the cytokine profile and the immune responses to thyroid an tigens of specific T cell clones (TCC) isolated from patients with Has himoto's thyroiditis (HT) and Graves' disease (GD). Antigen-specific T CC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or hu man recombinant TSH-receptor extracellular domain (TSH-R), and/or thei r respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patient s were reactive to TSH-R. TPO epitopes 100-119 and 625-644 were recogn ized by 75% of HT-derived clones, whereas TSH-R epitopes 158-176, 207- 222, and 343-362/357-376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-gamm a], Th1 (secreting IFN-gamma) and Th2 (secreting IL-4 and/or IL-5). Tu mor necrosis factor-beta and IL-10 were produced by all subsets. The s pecific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th 2 clones (82%) were reactive to TPO and were established from peripher al blood. All these clones produced IL-5, and 64% produced IL-4 and IL -10. Interestingly, IFN-gamma was highly produced by TPO- or Tg-specif ic clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TP O and TSH-R molecules and support the concept that immunodominant T ce ll epitopes are located on amino acid residues 100-119 and 625-644 of TPO in HT and amino acid residues 158-176, 207-222 and 343-362/357-376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-spe cific clones with Th1 phenotype appear to be involved in the pathogene sis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD .