The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function.
The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function.
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作者：
Gerold KD;Zheng P;Rainbow DB;Zernecke A;Wicker LS;Kissler S
CTLA4 基因变异与多种自身免疫性疾病相关，包括 1 型糖尿病。发现 CTLA4 易感性等位基因产生的编码可溶性 CTLA-4 (sCTLA-4) 的 mRNA 水平相对于全长异构体降低，其功能后果尚不清楚。在本研究中，我们研究了 sCTLA-4 对免疫调节的贡献，旨在阐明 CTLA4 与疾病相关的功能基础。为了模拟与疾病相关的 CTLA4 剪接变异，我们生成了 NOD 小鼠，其中 sCTLA-4 mRNA 通过 RNA 干扰而沉默。我们发现 sCTLA-4 的缺失会损害调节性 T (Treg) 细胞的功能。这种功能缺陷至少部分归因于 sCTLA-4 敲低 (KD) Treg 细胞未能下调树突状细胞共刺激。与野生型Treg细胞相比，sCTLA-4 KD Treg细胞未能抑制将CD4+CD45RBhi细胞转移至NOD.SCID动物中诱导的结肠炎。此外，sCTLA-4表达的减少加速了转基因小鼠自身免疫性糖尿病的发生。我们的结果表明，sCTLA-4 通过增强 Treg 细胞的功能来参与免疫调节。在 NOD 模型中沉默该剪接变体的功能结果为 CTLA4 变异与自身免疫的关联提供了解释。易感性等位基因的较低 sCTLA-4 表达可能直接影响 Treg 细胞的抑制能力，从而调节疾病风险。我们前所未有的方法确立了对与自身免疫相关的剪接变异进行建模的可行性。
CTLA4 gene variation associates with multiple autoimmune disorders, including type 1 diabetes. The CTLA4 susceptibility allele was found to generate decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the full-length isoform, the functional consequence of which is as yet unknown. In this study, we investigated the contribution of sCTLA-4 to immune regulation with the aim to elucidate the functional basis of the disease association of CTLA4. To model the disease-associated splicing variation of CTLA4, we generated NOD mice in which sCTLA-4 mRNA is silenced by RNA interference. We found that loss of sCTLA-4 impairs the function of regulatory T (Treg) cells. This functional defect could be attributed, at least in part, to the failure of sCTLA-4 knockdown (KD) Treg cells to downregulate dendritic cell costimulation. sCTLA-4 KD Treg cells, in contrast with wild-type Treg cells, failed to inhibit colitis induced by transfer of CD4+CD45RBhi cells into NOD.SCID animals. Furthermore, diminished sCTLA-4 expression accelerated the onset of autoimmune diabetes in transgenic mice. Our results demonstrate that sCTLA-4 participates in immune regulation by potentiating the function of Treg cells. The functional outcome of silencing this splice variant in the NOD model provides an explanation for the association of CTLA4 variation with autoimmunity. Lower sCTLA-4 expression from the susceptibility allele may directly affect the suppressive capacity of Treg cells and thereby modulate disease risk. Our unprecedented approach establishes the feasibility of modeling splicing variations relevant to autoimmunity.