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

被引:13
作者
Greidinger, Eric L. [1 ,2 ]
Zang, Yun Juan [1 ]
Jaimes, Kimberly [1 ]
Martinez, Laisel [2 ]
Nassiri, Mehdi [3 ]
Hoffman, Robert W. [1 ,2 ,4 ]
机构
[1] Univ Miami, Div Rheumatol & Immunol, Dept Med, Miller Sch Med, Miami, FL 33101 USA
[2] Vet Affairs Med Ctr, Miami, FL 33125 USA
[3] Univ Miami, Dept Pathol, Miller Sch Med, Miami, FL 33101 USA
[4] Univ Miami, Dept Microbiol & Immunol, Miller Sch Med, Miami, FL 33101 USA
关键词
D O I
10.4049/jimmunol.180.12.8444
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:8444 / 8454
页数:11
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