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.
Division of Immunology and Rheumatology, Department of Internal Medicine, University of Missouri, Columbia, MO 65212, USA.
Mihiri
M
De Silva-Udawatta
Senthil R
SR
Kumar
Eric L
EL
Greidinger
Robert W
RW
Hoffman
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003001:Cloning, Molecular / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D040681:Structural Homology, Protein; D014162:Transfection; D055517:snRNP Core Proteins
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C490688:SNRNP70 protein, human; D055517:snRNP Core Proteins