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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 Disease¹

Eric L. Greidinger^*,, Yun Juan Zang^*, Kimberly Jaimes^*, Laisel Martinez, Mehdi Nassiri and Robert W. Hoffman^2,*,,

^* Division of Rheumatology and Immunology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33101; Miami Veterans Affairs Medical Center, Miami, FL 33125; Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33101; and Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33101

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-β (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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health, Lupus Foundation of America, Lupus Research Institute, and Department of Veterans Affairs.

² Address correspondence and reprint requests to Dr. Robert W. Hoffman, Division of Rheumatology and Immunology, University of Miami, 1120 N.W. 14th Street (D4-10), Miami, FL 33136. E-mail address: rhoffman{at}med.miami.edu

³ Abbreviations used in this paper: MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; RBD, RNA-binding domain; Tg, transgenic; TRB, TCR-β; MC, medium control.