FOXP3 Renders Activated Human Regulatory T Cells Resistant to Restimulation-induced Cell Death by Suppressing SAP Expression

Overview

Journal Cell Immunol

Publisher Elsevier

Specialties Allergy & Immunology
Cell Biology

Date 2018 Feb 19

PMID 29454648

Citations 9

Authors

Gil Katz

Kelsey Voss

Toria F Yan

Yong Chan Kim

Robert L Kortum

David W Scott

Andrew L Snow

Affiliations

Soon will be listed here.

Abstract

Restimulation-induced cell death (RICD) is an apoptotic program that regulates effector T cell expansion, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Although CD4 regulatory T cells (Tregs) consume IL-2 and experience frequent TCR stimulation, they are highly resistant to RICD. Resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcription factor, although the mechanism remains unclear. T cells from patients with X-linked lymphoproliferative disease (XLP-1), that lack the adaptor molecule SLAM-associated protein (SAP), are also resistant to RICD. Here we demonstrate that normal Tregs express very low levels of SAP compared to conventional T cells. FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter. Indeed, ectopic SAP expression restores RICD sensitivity in human FOXP3 Tregs. Our findings illuminate the mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence.

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