HUMAN SELF-REACTIVE T-CELL CLONES EXPRESSING IDENTICAL T-CELL RECEPTOR-BETA CHAINS DIFFER IN THEIR ABILITY TO RECOGNIZE A CRYPTIC SELF-EPITOPE

Recognition of self-antigens by T lymphocytes is a central event in au toimmunity. Understanding of the molecular interactions between T cell receptors (TCR) and self-epitopes may explain how T cells escape thym ic education and initiate an autoimmune reaction. We have studied five human in vivo activated T cell clones specific for the region 535-551 of human thyroid peroxidase (TPO) established from a Graves' patient. Three clones (37, 72, and 73) expressed identical TCR beta and alpha chains rearranging V beta 1.1 and V alpha 15.1, and were considered si ster clones. Clone 43 differed from clone 37 and its sisters in the J alpha region only. Clone NP-7 expressed V beta 6.5 but rearranged two in-frame TCR alpha chain, both using the V alpha 22.1 segment. Fine ep itope mapping using nested peptides showed that clones using identical TCR beta chains, identical V alpha, but a different J alpha recognize d distinct, nonoverlapping epitopes in the TPO 535-551 region. This fi nding shows that a different J alpha region alone leads to a heterogen eous pattern of recognition. This indicates that the ''restricted'' TC R V region usage sometimes found in autoimmune diseases may not always correspond to identical epitope recognition. To confirm that clones 3 7 (and its sisters) and 43 recognize different epitopes, the T cell cl ones were stimulated with a TPO-transfected autologous Epstein-Barr vi rus (EBV) cell Line (TPO-EBV) that presents TPO epitopes after endogen ous processing. Only clone 37 and its sisters recognizes the TPO-EBV c ell Line, suggesting that the epitope recognized by clone 43 is not pr esented upon endogenous processing. We have shown that thyroid epithel ial cells (TEC), the only cells that produce TPO, express HLA class II molecules in Graves' disease and can act as antigen-presenting cells, presenting TPO after endogenous processing to autoantigen-reactive T cell clones. We tested, therefore, whether autologous TEC induced the same pattern of stimulation as TPO-EBV; T cell clone 37 recognizes the TEC, whereas it is stimulated poorly by the TPO loaded to autologous peripheral blood mononuclear cells (PBMC). Clone 43, which fails to re cognize the TPO-EBV, also fails to recognize the TEC, but is activated by exogenous TPO presented by autologous PBMC. These results show tha t exogenous versus endogenous processing in vivo generates a different TPO epitope repertoire, producing a ''cryptic'' epitope (epitope not always available for recognition). Our findings define a route by whic h human self-reactive T cells may escape thymic selection and become a ctivated in vivo, thus possibly leading to autoimmunity.