Ets1, a Key Regulator of TFH2 Cell Differentiation

E26 transformation-specific-1 (Ets1) is a member of the Ets family of transcription factors and plays important functions in the development, proliferation, and survival of immune cells. Single nucleotide polymorphisms (SNPs) in the ETS1 gene are highly discovered in Systemic Lupus Erythematosus (SLE) patients; however, the consequences of these SNPs remain unclear. Here we show Ets1 deficient (Ets1 KO) mice develop SLE-like disease, similar to human patients. Autoimmunity was T cell dependent as deletion of Ets1 in T cells but not B cells or Dendritic cells (DCs) recapitulated disease. T follicular helper (TFH) cells contributed to disease as they were both increased and showed correlation with disease severity. Furthermore, we report, for the first time in mice, a pathogenic increase of T follicular helper type 2 (TFH2) cells which caused type 2 hyperglobulinemia in Ets1 KO mice. Mechanistically, the increase of TFH cells was due to enhanced TFH differentiation. In line with this, Ets1 KO T naïve cells showed upregulation of a TFH transcriptome even before receiving activation stimulations. Finally, we validated these results in Korean SLE patients. Individuals with SLE had low Ets1 levels and high TFH and TFH2 cell frequencies. Furthermore, Ets1 levels showed inverse correlation with disease severity and TFH and TFH2 frequencies. Thus, we discovered Ets1 protects both mice and humans from SLE disease by suppressing TFH and TFH2 cell differentiation, and propose Ets1 and TFH2 cells as novel targets for SLE therapy. This study was supported from the Institute for Basic Science (IBS; IBS-R005), Republic of Korea.2