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.
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.
Latham
Kary A
KA
Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Whittington
Karen B
KB
Zhou
Ruohong
R
Qian
Zhaohui
Z
Rosloniec
Edward F
EF
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000209:etiology* / Q000276:immunology; D015551:Autoimmunity; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003094:Collagen / Q000009:adverse effects; D024043:Collagen Type II / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D007596:Joints / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D024043:Collagen Type II; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D016056:Immunodominant Epitopes; D003094:Collagen