JUNCTIONAL REGION SEQUENCES OF T-CELL RECEPTOR BETA-CHAIN GENES EXPRESSED BY PATHOGENIC ANTI-DNA AUTOANTIBODY-INDUCING HELPER T-CELLS FROM LUPUS MICE - POSSIBLE SELECTION BY CATIONIC AUTOANTIGENS
JUNCTIONAL REGION SEQUENCES OF T-CELL RECEPTOR BETA-CHAIN GENES EXPRESSED BY PATHOGENIC ANTI-DNA AUTOANTIBODY-INDUCING HELPER T-CELLS FROM LUPUS MICE - POSSIBLE SELECTION BY CATIONIC AUTOANTIGENS
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DOI：
10.1073/pnas.88.24.11271
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发表时间：
1991-12-01
影响因子：
11.1
通讯作者：
DATTA, SK
中科院分区：
文献类型：
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作者：
ADAMS, S;LEBLANC, P;DATTA, SK
我们从患有狼疮性肾炎的10只（SWR x NZB）F1（SNF 1）小鼠的脾脏中拯救了体内活化的T细胞，并克隆了268个T细胞系和杂交瘤。这些T细胞克隆中只有12%具有优先增加致病性抗DNA自身抗体产生的功能能力。其中，16个辅助T细胞（T（h）-细胞）克隆，主要是CD 4+，并具有最强的自身抗体诱导能力进行了分析的T细胞受体（TCR）β链基因的使用。16个T（h）细胞克隆中有7个表达β链可变区（V（beta））V（beta）8（8.2或8.3）基因，3个表达V（beta）4，而2个克隆各自使用V（beta）1或V（beta）2或V（beta）14基因，表明TCR基因使用存在一定限制。尽管是异质的，但这些T（h）细胞克隆所使用的TCR β链基因的V-D-J连接区序列总是编码一个或多个带负电荷的残基（天冬氨酸或谷氨酸），这些残基在大多数情况下是通过添加未指明的核苷酸（N）产生的。代表性的致病性自身抗体诱导T（h）细胞克隆可以迅速诱导狼疮性肾炎的发展时，注射到年轻的prenephritic SNF 1小鼠。在其TCR β链连接处（互补决定区CDR 3）表达阴离子残基的致病性自身抗体诱导T（h）细胞可能被它们优先帮助的抗DNA B细胞呈递的某些阳离子自身抗原肽所选择。这些结果提供了一个线索的性质的主要自身抗原，可能会驱动狼疮的致病性自身免疫反应。
We rescued from the spleens of 10 (SWR x NZB)F1(SNF1) mice with lupus nephritis the T cells that were activated in vivo and cloned 268 T-cell lines and hybridomas. Only 12% of these T-cell clones had the functional ability to preferentially augment the production of pathogenic anti-DNA autoantibodies. Among these, 16 helper T-cell (T(h)-cell) clones that were mostly CD4+ and had the strongest autoantibody-inducing ability were analyzed for T-cell receptor (TCR) beta-chain gene usage. Seven of the 16 T(h)-cell clones expressed beta-chain variable region (V(beta)) V(beta)8 (8.2 or 8.3) genes and three expressed V(beta)4, whereas two clones each used a V(beta)1 or V(beta)2 or V(beta)14 gene, suggesting some restriction in TCR gene usage. Although heterogeneous, the V-D-J junctional region sequences of TCR beta-chain genes used by these T(h)-Cell clones invariably encoded one or more negatively charged residues (aspartic or glutamic acid) that had been generated in most cases by unspecified nucleotide (N) additions. Representative pathogenic autoantibody-inducing T(h)-cell clones could rapidly induce the development of lupus nephritis when injected into young prenephritic SNF1 mice. The pathogenic autoantibody-inducing T(h) cells expressing the anionic residues in their TCR beta-chain junctions (complementarity-determining region CDR3) were probably selected by some cationic autoantigenic peptide presented by the anti-DNA B cells they preferentially helped. These results offer a clue regarding the nature of the primary autoantigen that may drive the pathogenic autoimmune response in lupus.