Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9560-5. doi: 10.1073/pnas.1017854108. Epub 2011 May 23.
The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23-dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity.
该 SNP(c.1142G > A;p.R381Q)位于白细胞介素-23 受体(IL-23R)中，可对多种炎症性疾病提供保护，这是自身免疫性疾病中最重要的人类遗传多态性之一。因此，我们试图确定该具有临床意义的变异的功能后果。我们发现，与 WT IL23R 个体相比，来自健康 R381Q IL23R 携带者的 CD4+CD45RO+和 CD8+T 细胞显示出 IL-23 依赖性 IL-17 和 IL-22 产生减少。这与循环 Th17 和 Tc17 细胞的比例降低有关。此外，与 WT CD8+T 细胞相比，R381Q IL23R 个体的 CD8+T 细胞显示出 IL-23 依赖性扩增和信号转导和转录激活因子 3(STAT3)激活减少。重要的是，与 IL23R 精氨酸等位基因相比，转染了 IL23R 谷氨酰胺变异体的细胞显示出 IL-23 介导的信号转导减少。我们的结果表明，R381Q IL23R 变体导致原发性人 CD4+和 CD8+T 细胞中选择性的、潜在有益的功能丧失改变，从而对自身免疫提供高度显著的保护。
