CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease.
Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with significant morbidity and premature mortality of unknown pathogenesis. In the present study, we characterized U1-70-kDa small nuclear ribonucleoprotein (70-kDa) autoantigen-specific T cells in a new murine model of MCTD. These studies defined 70-kDa-reactive T cell Ag fine specificities and TCR gene usage in this model. Similar to patients with MCTD, CD4(+) T cells can be readily identified from 70-kDa/U1-RNA-immunized HLA-DR4-transgenic mice. Using both freshly isolated CD4(+) T cells from spleen and lung, and T cell lines, we found that the majority of these T cells were directed against antigenic peptides residing within the RNA-binding domain of 70 kDa. We also found that TCR-beta (TRB) V usage was highly restricted among 70-kDa-reactive T cells, which selectively used TRBV subgroups 1, 2, 6, 8.1, 8.2, and 8.3, and that the TRB CDR3 had conserved sequence motifs which were shared across different TRBV subgroups. Finally, we found that the TRBV and CDR3 regions used by both murine and human 70-kDa-specific CD4(+) T cells were homologous. Thus, T cell recognition of the 70-kDa autoantigen by HLA-DR4-transgenic mice is focused on a limited number of T cell epitopes residing primarily within the RBD of the molecule, using a restricted number of TRBV and CDR3 motifs that are homologous to T cells isolated from MCTD patients.
Division of Rheumatology and Immunology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
Eric L
EL
Greidinger
Yun Juan
YJ
Zang
Kimberly
K
Jaimes
Laisel
L
Martinez
Mehdi
M
Nassiri
Robert W
RW
Hoffman
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015234:HLA-A Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008947:Mixed Connective Tissue Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C490687:Snrnp70 protein, mouse