Single-nucleotide polymorphisms in ETS1 are associated with systemic lupus erythematosus (SLE). Ets1^−/− mice develop SLE-like symptoms, suggesting that dysregulation of this transcription factor is important to the onset or progression of SLE. We used conditional deletion approaches to examine the impact of Ets1 expression in different immune cell types. Ets1 deletion on CD4⁺ T cells, but not B cells or dendritic cells, resulted in the SLE autoimmunity, and this was associated with the spontaneous expansion of T follicular helper type 2 (Tfh2) cells. Ets1^−/− Tfh2 cells exhibited increased expression of GATA-3 and interleukin-4 (IL-4), which induced IgE isotype switching in B cells. Neutralization of IL-4 reduced Tfh2 cell frequencies and ameliorated disease parameters. Mechanistically, Ets1 suppressed signature Tfh and Th2 cell genes, including Cxcr5, Bcl6, and Il4ra, thus curbing the terminal Tfh2 cell differentiation process. Tfh2 cell frequencies in SLE patients correlated with disease parameters, providing evidence for the relevance of these findings to human disease.

ETS1中的单核苷酸多态性与系统性红斑狼疮（SLE）相关。Ets1 ^-/-小鼠出现SLE样症状，表明该转录因子的失调对SLE的发作或进展很重要。我们使用条件删除方法来检查在不同的免疫细胞类型中Ets1表达的影响。CD4 ⁺ T细胞而不是B细胞或树突状细胞上Ets1缺失导致SLE自身免疫，这与T滤泡辅助2型（Tfh2）细胞的自发扩增有关。Ets1 ^-/-Tfh2细胞显示GATA-3和白介素4（IL-4）的表达增加，从而诱导B细胞中的IgE同种型转换。IL-4的中和降低了Tfh2细胞的频率并改善了疾病参数。机械地，ETS1抑制签名TFH和Th2细胞的基因，包括CXCR5，Bcl6转录因子，和Il4ra，从而遏制终端Tfh2细胞分化过程。SLE患者的Tfh2细胞频率与疾病参数相关，为这些发现与人类疾病的相关性提供了证据。