The Transcription Factor EGR2 Plays a Central Role in the Expansion and Function of TCRαβ ⁺ CD4 ⁻ CD8 ⁻ Double Negative T Cells in lpr Lupus Mice

TCRαβ + CD4 − CD8 − double negative T (TCRβ + DNT) cells are highly accumulated in human and murine lupus, although the origin and function of TCRβ + DNT cells remains largely elusive and controversy. Remarkably, conditional deletion of Egr2 in lymphocytes significantly reduced TCRβ + NK1.1 − DNT cells, the dominant DNT type in B6/ lpr mice. TCRβ + DNT cells of B6/ lpr mice surprisingly had a lower expression of IFNγ, IL‐17, and IL‐10 compared to normal B6 mice, which was likely due to high CD138 expression in the TCRβ + DNT cells of B6/ lpr mice. Conditionally deleting Egr2 in B6/ lpr mice increased IFNγ and IL‐10, but not IL‐17 in TCRβ + DNT cells. Egr2 deletion suppressed IL‐17 expression in TCRγδ + DNT cells, the major IL‐17‐expressing DNT cells in B6/ lpr mice. The scRNA‐seq analysis of DNT cells from Egr2 − /− B6/ lpr (CD2‐Cre Egr2 − /− B6/ lpr , EK) and control Egr2 fl/fl B6/ lpr (EF) mice revealed a striking segregation of DNT clusters with distinct transcriptional profiles, identified as EK_dominant and EF_dominant DNT clusters. Egr2 deletion in B6/ lpr mice seemingly normalised Helios, Ly6C, and Ly6A/E expression to levels similar to B6 mice, implying that inhibition of EGR2 can effectively correct the abnormalities in DNT cells of B6/ lpr mice. Further, we found that conditional Egr2 deletion reduced TCRβ + DN thymocytes in B6/ lpr mice and suppressed DNT‐cell generation from in vitro cultured splenic CD8 + T cells, suggesting that EGR2 might promote TCRβ + DNT cells in lpr mice at both the thymic and peripheral stages. Together, this study is the first to reveal a critical role of EGR2 in regulating the expansion, heterogeneity, and function of TCRβ + DNT cells in lupus mice.