Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune T cell receptor alpha chain.
Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune T cell receptor alpha chain.
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狼疮中核小体自身表位的混杂呈现和识别：自身免疫 T 细胞受体 α 链的作用。
DOI：
10.1084/jem.187.3.367
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Datta,SK
中科院分区：
文献类型：
--
作者：
Shi,Y;Kaliyaperumal,A;Lu,L;Southwood,S;Sette,A;Michaels,MA;Datta,SK
对核小体自身表位特异的T细胞在狼疮小鼠中选择性扩增，这些Th细胞驱动自身免疫B细胞产生致病性抗核抗体。我们将一个代表性的、对核小体核心组蛋白肽H471- 94特异性的致病性自身抗体诱导Th克隆的TCR-α和-β链基因转染到TCR阴性的受体细胞中。尽管自身免疫TCR最初来源于SNF 1（I-Ad/q）小鼠，但转染子可以识别由所有测试的单倍型的携带APC的I-A分子以及人DR分子呈递的核小体自身表位。竞争分析表明，自身表位结合的MHC II类沟。最值得注意的是，核小体肽表位的MHC非限制性识别是由狼疮TCR-α链赋予的，即使它与不相关特异性的TCR-β链配对。其他几种疾病相关的Th克隆和狼疮小鼠的脾T细胞具有类似的特性。这些小鼠狼疮Th克隆的TCR-α链在其CDR中具有相似的基序和带电荷的残基，甚至在人狼疮Th克隆的TCR-α链中也存在相似的基序。狼疮TCR-α链可能以相对高的亲和力/亲合力接触与MHC复合的核小体肽，以维持TCR信号传导，因为CD 4辅助受体不是混杂识别所必需的。事实上，系统性红斑狼疮患者中，致病性自身抗体诱导的CD 4阴性TCR-αβ+Th细胞扩增。这些结果对狼疮核小体特异性T细胞的胸腺选择和外周扩增有影响。他们还表明，普遍致耐受性表位可以设计用于治疗具有不同HLA等位基因的狼疮患者。我们建议将带有通用表位的核小体和其他抗原命名为“Pantigens”（用于混杂抗原）。
T cells specific for nucleosomal autoepitopes are selectively expanded in lupus mice and these Th cells drive autoimmune B cells to produce pathogenic antinuclear antibodies. We transfected the TCR-α and -β chain genes of a representative, pathogenic autoantibody-inducing Th clone specific for the nucleosomal core histone peptide H471–94into TCR-negative recipient cells. Although the autoimmune TCRs were originally derived from SNF1 (I-Ad/q) mice, the transfectants could recognize the nucleosomal autoepitope presented by APC-bearing I-A molecules of all haplotypes tested, as well as human DR molecules. Competition assays indicated that the autoepitopes bound to the MHC class II groove. Most remarkably, MHC-unrestricted recognition of the nucleosomal peptide epitope was conferred by the lupus TCR-α chain even when it paired with a TCR-β chain of irrelevant specificity. Several other disease-relevant Th clones and splenic T cells of lupus mice had similar properties. The TCR-α chains of these murine lupus Th clones shared related motifs and charged residues in their CDRs, and similar motifs were apparent even in TCR-α chains of human lupus Th clones. The lupus TCR-α chains probably contact the nucleosomal peptide complexed with MHC with relatively high affinity/avidity to sustain TCR signaling, because CD4 coreceptor was not required for promiscuous recognition. Indeed, pathogenic autoantibody-inducing, CD4-negative, TCR-αβ+Th cells are expanded in systemic lupus erythematosus. These results have implications regarding thymic selection and peripheral expansion of nucleosome-specific T cells in lupus. They also suggest that universally tolerogenic epitopes could be designed for therapy of lupus patients with diverse HLA alleles. We propose to designate nucleosomes and other antigens bearing universal epitopes “Pantigens” (for promiscuous antigens).