A T cell-binding fragment of fibrinogen can prevent autoimmunity.
A T cell-binding fragment of fibrinogen can prevent autoimmunity.
复制标题
纤维蛋白原的 T 细胞结合片段可以预防自身免疫。
DOI：
10.1016/j.jaut.2009.11.017
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发表时间：
2010
影响因子：
12.8
通讯作者：
Maverakis,Ema
中科院分区：
文献类型：
--
作者：
Takada,Yoshikazu;Ono,Yoko;Saegusa,Jun;Sagusa,Jun;Mitsiades,Constantine;Mitsiades,Nicholas;Tsai,Jean;He,Yong;Maningding,Ernest;Coleman,Annie;Ramirez-Maverakis,Dalila;Rodrigues,Raphael;Rodriquez,Raphael;Takada,Yoko;Maverakis,Ema
纤维蛋白原γ链的C-末端结构域（γC）已显示与整合素αIIbβ3、αMβ2和αVβ3结合。也有报道称，γC的αMβ2结合位点衍生的肽可以抑制多发性硬化的动物模型，实验性自身免疫性脑脊髓炎（EAE）。我们在399位截短了γC，去除了血栓前αIIbβ3结合位点。我们发现，这种截短的γC，称为γ C399 tr，可以结合活化的T细胞。此外，当用抗原和APC刺激时，用γ C399 tr孵育的T细胞分泌较少的IFN-γ;然而，当用抗CD 3和抗CD 28抗体的混合物非特异性刺激T细胞时，细胞因子分泌不变。因此，仅抗原依赖性T细胞活化被γ C399 tr抑制。γ C399 tr经腹腔给药后，可有效抑制主动诱发的EAE，并逆转正在进行的疾病。我们假设γ C399 tr抑制自身反应性免疫应答的能力是其结合整合素的能力的结果。这种活性不仅仅依赖于αMβ2整合素结合位点。当多聚丙氨酸取代αMβ2结合位点时，γ C390 polyA仍能抑制EAE。据我们所知，这是第一次证明T细胞可以结合纤维蛋白（原），一种重要的细胞外基质蛋白，沉积在炎症部位。我们的研究结果还确定γ C399 tr作为一种新的治疗分子。
The C-terminal domain of the fibrinogen γ chain (γC) has been shown to bind to the integrins αIIbβ3, αMβ2 and αVβ3. It has also been reported that a peptide derived from the αMβ2-binding site of γC can suppress an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Here we have truncated γC at position 399 to remove the prothrombotic αIIbβ3-binding site. We show that this truncated version of γC, termed γC399tr, can bind to activated T cells. In addition, T cells incubated with γC399tr secreted less IFN-γ when stimulated with antigen and APC; however, cytokine secretion was unaltered when T cells were stimulated non-specifically with a mixture of anti-CD3 and anti-CD28 antibodies. Thus, only antigen-dependent T cell activation is inhibited by γC399tr. When administered intraperitoneally, γC399tr potently inhibited actively induced EAE and reversed ongoing disease. We hypothesize that the ability of γC399tr to inhibit autoreactive immune responses is a result of its ability to bind integrins. This activity was not solely dependent on the αMβ2 integrin-binding site. When polyalanine was substituted for the αMβ2-binding site, the resulting γC390polyA was still able to inhibit EAE. To our knowledge, this is the first demonstration that T cells can bind to fibrin (ogen), an important extracellular matrix protein that is deposited at sites of inflammation. Our results also identify γC399tr as a novel therapeutic molecule.