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-CreEgr2 -/-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.