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

摘要

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 DRl-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 Thl 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 Cll-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-speciflc T cells in the pathogenesis of CIA.