Cloned human TCR from patients with autoimmune disease can respond to two structurally distinct autoantigens

There is increasing evidence that the TCR can have significant plasticity in the range of Ags that a single receptor can recognize. Although it has been proposed that such TCR plasticity might contribute to autoimmunity, there have been few studies examining this possibility in either animal models or human disease. In the present study, we examined human T cell clones that were generated against two structurally dissimilar proteins, U1-70 kDa and Smith-B, that are physically associated in the U1-small nuclear ribonucleoprotein complex and that are frequent targets of autoantibodies and T cells in the same lupus patient. We found that the TCR from all clones isolated had substantial sequence homology within their complementarity-determining region 3. We molecularly cloned and expressed individual TCR/A and TCR/B genes in a TCR-negative human cell line J.RT3-T3.5. We then examined the interaction between the TCR and U1-70 kDa and Smith-B antigenic peptides. We found that there was plasticity or degeneracy of the TCR reactive with these lupus autoantigens in that two structurally dissimilar lupus autoantigenic peptides could stimulate a single TCR. These studies support an important role of plasticity of the TCR in the development of human autoimmunity.