T cell immunity in connective tissue disease patients targets the RNA binding domain of the U1-70kDa small nuclear ribonucleoprotein.
Although the T cell dependence of autoimmune responses in connective tissue diseases has been well established, limited information exists regarding the T cell targeting of self Ags in humans. To characterize the T cell response to a connective tissue disease-associated autoantigen, this study generated T cell clones from patients using a set of peptides encompassing the entire linear sequence of the 70-kDa subunit of U1 snRNP (U1-70kDa) small nuclear ribonucleoprotein. Despite the ability of U1-70kDa to undergo multiple forms of Ag modification that have been correlated with distinct clinical disease phenotypes, a remarkably limited and consistent pattern of T cell targeting of U1-70kDa was observed. All tested T cell clones generated against U1-70kDa were specific for epitopes within the RNA binding domain (RBD) of the protein. High avidity binding of the RBD with U1-RNA was preserved with the disease-associated modified forms of U1-70kDa tested. The high avidity interaction between the U1-RBD on the polypeptide and U1-RNA may be critical in immune targeting of this region in autoimmunity. The T cell autoimmune response to U1-70kDa appears to have less diversity than is seen in the humoral response; and therefore, may be a favorable target for therapeutic intervention.
Greidinger
Eric L
EL
Division of Immunology and Rheumatology, University of Missouri, Columbia, MO 65212, USA.
Foecking
Mark F
MF
Schäfermeyer
Kim R
KR
Bailey
Craig W
CW
Primm
Shannon L
SL
Lee
David R
DR
Hoffman
Robert W
RW
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D001782:Blood Donors; D002999:Clone Cells; D003240:Connective Tissue Diseases / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010449:Peptide Mapping; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012342:RNA, Small Nuclear / Q000276:immunology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010446:Peptide Fragments; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; C490688:SNRNP70 protein, human; C405483:U1 small nuclear RNA; D000409:Alanine