Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance
Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance
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DOI：
10.1172/jci200318310
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Laufer, TM
中科院分区：
文献类型：
--
作者：
Busser, BW;Adalr, BS;Laufer, TM
在人类和小鼠的系统性红斑狼疮中，CD4(+)辅助T细胞在抗核自身抗体的产生中起着关键作用。一个关键的问题是，这种帮助是来自不同的自身反应性CD4(+)T细胞，还是来自有限特异性的选定数量的T细胞。我们使用慢性移植物抗宿主病模型来确定诱导自身抗体反应所需的CD4(+)T细胞谱系的多样性。通过转移克隆性限制性和克隆性多样性的MHC II类反应性CD4(+)T细胞，我们发现B细胞对核抗原的耐受性丧失有两个不同的成分，即不同的CD4(+)细胞需求。激活有限的CD4(+)T细胞足以扩增无能的抗双链DNA B细胞和产生IgM自身抗体。出乎意料的是，我们发现CD4(+)T细胞的多样性对于CD4(+)T细胞进入毛囊和产生同型转换的免疫球蛋白自身抗体是必需的。重要的是，将两个有限的T细胞组合在一起可以提供足够的CD4(+)T细胞多样性来驱动抗核抗体的产生。这些数据表明，需要一个不同的CD4(+)T细胞谱系来产生能够介导全身自身免疫的持续效应B细胞反应。
CD4(+) helper T cells play a critical role in the production of the antinuclear autoantibodies that characterize systemic lupus erythematosus in mice and humans. A key issue is whether this help is derived from a diverse repertoire of autoreactive CD4(+)T cells or from a select number of T cells of limited specificity. We used the chronic graft-versus-host disease model to define the diversity of the CD4(+)T cell repertoire required to induce the autoantibody response. By transferring clonally restricted versus clonally diverse populations of MHC class II-reactive CD4(+)T cells, we show that the loss of B cell tolerance to nuclear antigens has two distinct components with different CD4(+) cell requirements. Activation of limited repertoires of CD4(+)T cells was sufficient for the expansion of anergized anti-double-stranded DNA B cells and production of IgM autoantibodies. Unexpectedly, we found that CD4(+)T cell diversity was necessary for CD4(+)T cell trafficking into the follicle and for the generation of isotype-switched IgG autoantibodies. Importantly, combining two limited repertoires of T cells provides sufficient CD4(+)T cell diversity to drive antinuclear Ab production. These data demonstrate that a diverse CD4(+)T cell repertoire is required to generate a sustained effector B cell response capable of mediating systemic autoimmunity.