Regulatory T cells evade restimulation-induced cell death by FOXP3-mediated repression of the SAP promoter.

Abstract

Abstract An efficient adaptive immune response relies on the rapid clonal expansion of effector T cells, paired with timely disposal of those cells in order to avoid damage to host tissues and maintain immune homeostasis. Restimulation-induced cell death (RICD) is one programmed apoptotic pathway that ensures effector T cell expansion remains in check, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). CD4+ regulatory T cells (Tregs) require IL-2 and experience frequent TCR stimulation, but are highly resistant to RICD. Although the mechanism remains unclear, previous work has shown that RICD resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcriptional repressor, the master regulator of Treg function. We have previously shown that T cells from patients with X-linked lymphoproliferative disease (XLP-1), caused by null mutations in the signaling adaptor molecule SLAM-associated protein (SAP), are resistant to RICD. In fact, SAP is required for optimal RICD in effector T cells. We now demonstrate that Tregs express very low levels of SAP compared to conventional T cells (Tconv). Using chromatin immunoprecipitation and reporter assays, we show that FOXP3 reduces SAP expression in Tregs by binding to and repressing the SH2D1A (SAP) promoter. Indeed, knockdown of FOXP3 restores SAP-driven RICD sensitivity in Tregs through a FAS ligand-dependent mechanism. Intriguingly, our preliminary data suggest that FOXP3 also confers RICD resistance in Tconv during initial rounds of activation-induced proliferation. Hence our results provide a mechanism by which FOXP3 confers resistance to RICD to help preserve Tregs and protect early effector Tconv cells.