Reduced self-reactivity of an autoreactive T cell after activation with cross-reactive non-self-ligand.
Reduced self-reactivity of an autoreactive T cell after activation with cross-reactive non-self-ligand.
复制标题
用交叉反应性非富含配体激活后自动反应性T细胞的自反应性降低。
DOI：
10.1084/jem.20020390
复制
发表时间：
2002-11-04
影响因子：
15.3
通讯作者：
Kuchroo, Vijay K
中科院分区：
文献类型：
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作者：
Munder, Markus;Bettelli, Estelle;Monney, Laurent;Slavik, Jacqueline M;Nicholson, Lindsay B;Kuchroo, Vijay K
自身反应性CD 4 + T淋巴细胞对于诱导自身免疫性疾病是至关重要的，但是由于T细胞受体（TCR）活化的简并性质，这些受体也对其他配体产生应答。自身反应性T细胞与其他非自身配体的相互作用已显示出激活和扩增自身反应性细胞并诱导自身免疫。为了理解与有效的非自身配体活化的幼稚交叉反应性T细胞的自身反应性的影响，我们已经产生了TCR转基因小鼠，其表达对包括自身抗原在内的许多配体具有广泛交叉反应性的TCR。初始转基因重组激活基因（Rag）2 − / − T细胞与有效的非自身配体的激活并没有导致对自身的反应性增强，但使这些T细胞对自身配体和抗CD 3无反应，尽管它们对非自身配体保留了一定程度的反应性。这些失敏细胞具有无反应性T细胞的许多特征。与干扰素（IFN）-γ相比，白细胞介素（IL）-2的产生选择性降低。p21 ras活性降低，p38丝裂原活化蛋白激酶（MAPK）相对保留，与已知的无反应性生化特征一致。令人惊讶的是，钙通量也受到影响，并且外源性IL-2无法逆转无能表型。因此，用过度刺激的非自身配体激活改变自身反应性T细胞的功能特异性而不改变TCR。这种机制可能保留了外周T细胞对外源抗原的有用反应性，同时消除了对自身的反应。
Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2 − / − T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self.