The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus

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Title
The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus
Author(s)
Chan Johng Kim; Choong-Gu Lee; Ju-Yang Jung; Ambarnil Ghosh; Syed Nurul Hasan; Sung-Min Hwang; Hyeji Kang; Changhon Lee; Gi-Cheon Kim; Dipayan Rudra; Chang-Hee Suh; Sin-Hyeog Im
Publication Date
2018-12
Journal
IMMUNITY, v.49, no.6, pp.1034 - 1048
Publisher
CELL PRESS
Abstract
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. Single-nucleotide polymorphisms in ETS1 are associated with systemic lupus erythematosus (SLE). Kim et al. show that Ets1 deletion in T cells, but not B cells or DCs, result in SLE-like humoral autoimmunity, which was due to the expansion of GATA-3+Bcl6+ Tfh2 cells and could be alleviated by neutralizing IL-4. Tfh2 frequencies in SLE patients correlate with disease parameters, suggesting therapeutic relevance for IL-4 blockade. ? 2018 Elsevier Inc
URI
https://pr.ibs.re.kr/handle/8788114/5370
ISSN
1074-7613
Appears in Collections:
Academy of Immunology and Microbiology(면역 미생물 공생 연구단) > Journal Papers (저널논문)
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