Section of Molecular Medicine, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA.
Clin Exp Immunol. 2012 Feb;167(2):346-55. doi: 10.1111/j.1365-2249.2011.04506.x.
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.
T 细胞受体转基因（TCR-Tg）小鼠特异性针对软骨蛋白聚糖 G1 结构域中的致关节炎 5/4E8 表位，已被生成并回交至易患关节炎的 BALB/c 背景中。尽管所有 TCR-Tg 系的 CD4(+)T 细胞中超过 90%为 5/4E8 特异性，但其中一个（TCR-TgA）对 G1 诱导或自发性关节炎高度敏感，而另一个（TCR-TgB）则不太敏感。在这里，我们研究了 TCR 信号的细微差异是否控制了关节炎的发作和严重程度。来自这两个 TCR-Tg 系的小鼠同时用纯化的重组人 G1（rhG1）结构域免疫，以引发软骨蛋白聚糖（PG）诱导的关节炎（GIA）。TCR-TgA 小鼠发生严重和早发性关节炎，而 TCR-TgB 小鼠发生较弱的关节炎，且发病时间延迟，尽管 TCR-TgB CD4(+)T 细胞表达的 TCR-Vβ4 链蛋白约多两倍。TCR-TgA 小鼠中更严重的关节炎与更高量的抗 G1 结构域特异性抗体、更多的 B 细胞和活化的辅助性 T 细胞有关。重要的是，TCR-TgB CD4(+)T 细胞对体外激活诱导的凋亡更敏感，这与它们更高的 TCR 和 CD3 表达以及增加的 TCR 信号强度有关。这些发现表明 TCR 信号强度决定了关节炎诱导的临床结果：“最佳”TCR 信号强度导致 TCR-TgA 小鼠中强烈的 T 细胞激活和严重的关节炎，而“超最佳”TCR 信号导致自我反应性 T 细胞的增强消除，从而导致疾病减弱。
