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

Title
The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus
Authors
Kim, Chan JohngLee, Choong-GuJung JYGhosh AHasan SNHwang SMKang HLee CKim GCRudra DSuh CHIM, SIN HYEOG
POSTECH Authors
IM, SIN HYEOG
Date Issued
18-Dec-2018
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). 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.
Keywords
IGE PRODUCTION; I INTERFERON; EXPRESSION; PATHOGENESIS; DEFICIENCY; ACTIVATION; LANDSCAPE; ENHANCER; PROMOTE; MICE
URI
http://oasis.postech.ac.kr/handle/2014.oak/94576
DOI
10.1016/j.immuni.2018.10.012
ISSN
1074-7613
Article Type
Article
Citation
IMMUNITY, vol. 49, no. 6, page. 1034 - +, 2018-12-18
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 IM, SIN HYEOG
Div of Integrative Biosci & Biotech
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