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首页> 外文期刊>The journal of immunology >Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes
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Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

机译：暴露于IL-15和IL-21可使自身反应性CD8 T细胞对自身免疫性糖尿病小鼠模型中的弱抗原作出反应并引起疾病

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Autoreactive CD8+ T lymphocytes play a key role in the pathogenesis of several autoimmune diseases. It is not yet well understood how autoreactive CD8+ T cells, which express TCRs with low reactivity toward self-Ags, gain the ability to respond to autoantigens to cause disease. Previously, we have shown that prior stimulation of CD8+ T cells with synergistic combinations of cytokines produced by the innate immune response, such as IL-21 and IL-15, induces Ag-independent proliferation. Such “cytokine-primed” CD8 T cells displayed increased responsiveness to limiting quantities of the cognate Ag. In this paper, we report that prior stimulation with IL-15 and IL-21 also enables CD8+ T cells to respond to weakly agonistic TCR ligands, resulting in proliferation, cytokine secretion, and cytolytic activity. Using a transgenic mouse model of autoimmune diabetes, we show that cytokine-primed autoreactive CD8+ T cells induce disease following stimulation by weak TCR ligands, but their diabetogenic potential is dependent on continuous availability of IL-15 in vivo. These findings suggest that inflammatory cytokines could facilitate the triggering of autoreactive CD8+ T cells by weak autoantigens, and this mechanism may have important implications for autoimmune diseases associated with microbial infections and chronic inflammation.
机译：自身反应性CD8 + T淋巴细胞在几种自身免疫性疾病的发病机理中起关键作用。尚未完全了解表达对自身Ags反应性低的TCR的自身反应性CD8 + T细胞如何获得对自身抗原引起疾病的反应能力。以前，我们已经显示，先天免疫反应（例如IL-21和IL-15）产生的细胞因子的协同组合会刺激CD8 + T细胞诱导非Ag增殖。此类“细胞因子引发”的CD8 T细胞显示出对有限数量的同源Ag的增强反应性。在本文中，我们报道了事先用IL-15和IL-21刺激还可以使CD8 + T细胞对弱激动性TCR配体作出反应，从而导致增殖，细胞因子分泌和细胞溶解活性。使用自身免疫性糖尿病的转基因小鼠模型，我们显示了细胞因子引发的自身反应性CD8 + T细胞在弱TCR配体刺激后诱导疾病，但其致糖尿病潜力取决于体内IL-15的持续可用性。这些发现表明，炎性细胞因子可以通过弱的自身抗原促进触发自身反应性CD8 + T细胞，并且这种机制可能对与微生物感染和慢性炎症相关的自身免疫性疾病具有重要意义。

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