T cell receptor (TCR) signal strength controls arthritis severity in proteoglycan-specific TCR transgenic mice

Authors

  • K. Olasz,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
    2. Department of Immunology and Biotechnology, Faculty of Medicine, University of Pécs, Hungary
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  • F. Boldizsar,

    Corresponding author
    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
    2. Department of Immunology and Biotechnology, Faculty of Medicine, University of Pécs, Hungary
      F. Boldizsar, Department of Immunology and Biotechnology, Faculty of Medicine, University of Pécs, Szigeti u. 12., Pécs, H-7643, Hungary. E-mail: ferenc.boldizsar@aok.pte.hu
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  • K. Kis-Toth,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
    2. Beth Israel Hospital (Rheumatology), Harvard Medical School
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  • O. Tarjanyi,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
    2. Department of Medical Biology, University of Pécs, Hungary
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  • A. Hegyi,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
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  • W. van Eden,

    1. Department of Infectious Diseases and Immunology, Division of Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, the Netherlands
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  • T. A. Rauch,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
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  • K. Mikecz,

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
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  • T. T. Glant

    1. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
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F. Boldizsar, Department of Immunology and Biotechnology, Faculty of Medicine, University of Pécs, Szigeti u. 12., Pécs, H-7643, Hungary. E-mail: ferenc.boldizsar@aok.pte.hu

Summary

T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and back-crossed into arthritis-prone BALB/c background. Although more than 90% of CD4+ T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4+ T cells expressed approximately twice more TCR-Vβ4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4+ T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: ‘optimal’ TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas ‘supra-optimal’ TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease.

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