rs2013278 in the multiple immunological-trait susceptibility locus CD28 regulates the production of non-functional splicing isoforms.
rs2013278 in the multiple immunological-trait susceptibility locus CD28 regulates the production of non-functional splicing isoforms.
复制标题
DOI：
10.1186/s40246-022-00419-7
复制
发表时间：
2022-10-21
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
CD28与CD80或CD86等配体结合，通过T细胞抗原受体表达抗原提呈细胞上的II类主要组织相容性复合体，为初始T细胞的活化提供关键的第二信号。大量研究表明，CD28在多种人类疾病的发病机制中起重要作用。最近的全基因组关联研究(GWASs)发现CD28是淋巴细胞和嗜酸性粒细胞计数、多发性硬化症、溃疡性结肠炎、乳糜泻、类风湿性关节炎、哮喘和原发性胆管炎的易感基因。然而，该基因座致病易感性的主要功能变异和分子机制仍有待阐明。本研究旨在从CD28基因座的数千个遗传变异中鉴定出主要的功能变异，并阐明其对CD28分子的功能影响。在与CD28基因座上的所有GWAS-Lead变异体表现出较强连锁不平衡(LD)的遗传变体中，位于与剪接调控相关的RBFox结合基序中的rs2013278被鉴定为与多种免疫学性状相关的主要功能变体。Rs2013278可直接调节CD28剪接异构体(CD28i和CD28Cas2)相对于全长CD28的相对内源性表达水平(P <； 0.05)。虽然在Jurkat T细胞上表达的全长CD2 8蛋白与CD80/CD86具有较高的结合亲和力，但CD2 8i和CD2 8ΔEX2编码的是功能丧失亚型。本研究首次证明了CD28具有一个共同的疾病相关的初级功能变体(即rs2013278)，该变体调节产生功能丧失亚型的CD28选择性剪接。它们通过诱导对自身抗原和过敏原过度反应的效应性T细胞无能来降低疾病风险。网上版载有补充材料，可在10.1186/s40246-022-00419-7查阅。
Ligation of CD28 with ligands such as CD80 or CD86 provides a critical second signal alongside antigen presentation by class II major histocompatibility complex expressed on antigen-presenting cells through the T cell antigen receptor for naïve T cell activation. A number of studies suggested that CD28 plays an important role in the pathogenesis of various human diseases. Recent genome-wide association studies (GWASs) identified CD28 as a susceptibility locus for lymphocyte and eosinophil counts, multiple sclerosis, ulcerative colitis, celiac disease, rheumatoid arthritis, asthma, and primary biliary cholangitis. However, the primary functional variant and molecular mechanisms of disease susceptibility in this locus remain to be elucidated. This study aimed to identify the primary functional variant from thousands of genetic variants in the CD28 locus and elucidate its functional effect on the CD28 molecule. Among the genetic variants exhibiting stronger linkage disequilibrium (LD) with all GWAS-lead variants in the CD28 locus, rs2013278, located in the Rbfox binding motif related to splicing regulation, was identified as a primary functional variant related to multiple immunological traits. Relative endogenous expression levels of CD28 splicing isoforms (CD28i and CD28Δex2) compared with full-length CD28 in allele knock-in cell lines generated using CRISPR/Cas9 were directly regulated by rs2013278 (P < 0.05). Although full-length CD28 protein expressed on Jurkat T cells showed higher binding affinity for CD80/CD86, both CD28i and CD28Δex2 encoded loss-of-function isoforms. The present study demonstrated for the first time that CD28 has a shared disease-related primary functional variant (i.e., rs2013278) that regulates the CD28 alternative splicing that generates loss-of-function isoforms. They reduce disease risk by inducing anergy of effector T cells that over-react to autoantigens and allergens. The online version contains supplementary material available at 10.1186/s40246-022-00419-7.
登录
查看更多内容
影响因子：
25.7
作者：
Cordell HJ;Fryett JJ;Ueno K;Darlay R;Aiba Y;Hitomi Y;Kawashima M;Nishida N;Khor SS;Gervais O;Kawai Y;Nagasaki M;Tokunaga K;Tang R;Shi Y;Li Z;Juran BD;Atkinson EJ;Gerussi A;Carbone M;Asselta R;Cheung A;de Andrade M;Baras A;Horowitz J;Ferreira MAR;Sun D;Jones DE;Flack S;Spicer A;Mulcahy VL;Byan J;Han Y;Sandford RN;Lazaridis KN;Amos CI;Hirschfield GM;Seldin MF;Invernizzi P;Siminovitch KA;Ma X;Nakamura M;Mells GF;PBC Consortia;Canadian PBC Consortium;Chinese PBC Consortium;Italian PBC Study Group;Japan-PBC-GWAS Consortium;US PBC Consortium;UK-PBC Consortium
通讯作者：
UK-PBC Consortium
影响因子：
4.6
作者：
Hitomi Y;Kojima K;Kawashima M;Kawai Y;Nishida N;Aiba Y;Yasunami M;Nagasaki M;Nakamura M;Tokunaga K
通讯作者：
Tokunaga K
影响因子：
25.7
作者：
Jones, DEJ;Watt, FE;James, OFW
通讯作者：
James, OFW
影响因子：
3.7
作者：
Kakoulidou, M.;Giscombe, R.;Wang, X.
通讯作者：
Wang, X.
影响因子：
56.9
作者：
FRASER, JD;IRVING, BA;WEISS, A
通讯作者：
WEISS, A