Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2024 Mar 9;15(1):2150. doi: 10.1038/s41467-024-46457-8.
Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4 T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5PD-1 Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.
精细映射和功能研究表明，CD28/CTLA4/ICOS 基因座中的非编码单核苷酸多态性 rs117701653 是类风湿关节炎和 1 型糖尿病的风险变异。在这里，我们使用 DNA 下拉、质谱分析、基因组编辑和 eQTL 分析，确定了与疾病相关的风险等位基因是功能性的，降低了其与抑制性染色体调节剂 SMCHD1 的亲和力，从而增强了健康供体记忆 CD4 T 细胞中诱导型 T 细胞共刺激物（ICOS）的表达。较高的 ICOS 表达伴随着外周辅助性 T 细胞（Tph）循环细胞的增加，在类风湿关节炎患者中，血液和关节液 Tph 细胞以及循环浆母细胞的增加也是如此。相应地，ICOS 结合和 rs117701653 风险等位基因的携带加速了 T 细胞分化为产生 IL-21 和 CXCL13 的 CXCR5PD-1 Tph 细胞。因此，对人类自身免疫中功能性非编码变异的机制剖析揭示了一个以前未定义的途径，ICOS 通过该途径调节 Tph 的发育和丰度。
