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.