Ex Vivo Characterization of the Autoimmune T Cell Response in the HLA-DR1 Mouse Model of Collagen-Induced Arthritis Reveals Long-Term Activation of Type II Collagen-Specific Cells and Their Presence in Arthritic Joints

• Published in: The Journal of immunology (1950) 2005-04, Vol.174 (7), p.3978-3985
• Main Authors: Latham, Kary A, Whittington, Karen B, Zhou, Ruohong, Qian, Zhaohui, Rosloniec, Edward F
• Format: Article
• Language: English
• Subjects: Animals; Arthritis - chemically induced; Arthritis - etiology; Arthritis - immunology; Autoimmunity; Chemotaxis, Leukocyte - immunology; Collagen - adverse effects; Collagen Type II - immunology; Cytokines - genetics; Disease Models, Animal; Epitopes, T-Lymphocyte - immunology; HLA-DR1 Antigen - genetics; HLA-DR1 Antigen - immunology; Humans; Immunodominant Epitopes; Joints - immunology; Joints - pathology; Lymphocyte Activation; Mice; Mice, Transgenic; Synovial Membrane - immunology; Synovial Membrane - pathology; T-Lymphocytes - immunology; Time Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.7.3978

Although the pathogenesis of collagen-induced arthritis (CIA), a model of rheumatoid arthritis, is mediated by both collagen-specific CD4(+) T cells and Ab specific for type II collagen (CII), the role of CII-specific T cells in the pathogenesis of CIA remains unclear. Using tetrameric HLA-DR1 with a covalently bound immunodominant CII peptide, CII(259-273), we studied the development of the CII-specific T cell response in the periphery and arthritic joints of DR1 transgenic mice. Although the maximum number of DR1-CII-tetramer(+) cells was detected in draining lymph nodes 10 days postimmunization, these T cells accounted for only 1% or less of the CD4(+) population. After day 10, their numbers gradually decreased, but were still detectable on day 130. Examination of TCR expression and changes in CD62L, CD44(high), and CD69 expression by these T cells indicated that they expressed a limited TCR-BV repertoire and had clearly undergone activation. RT-PCR analysis of cytokine expression by the tetramer(+) T cells compared with tetramer(-) cells indicated the tetramer(+) cells expressed high levels of Th1 and proinflammatory cytokines, including IL-2, IFN-gamma, IL-6, TNF-alpha, and especially IL-17. Additionally, analysis of the synovium from arthritic paws indicated that the same CD4(+)/BV8(+)/BV14(+)/tetramer(+) T cells were present in the arthritic joints. These data demonstrate that although only small numbers of CII-specific T cells are generated during the development of CIA, these cells express very high levels of cytokine mRNA and appear to preferentially migrate to the arthritic joint, indicating a potential direct role of CII-specific T cells in the pathogenesis of CIA.