Mechanisms of FOXP3-Mediated Resistance to Restimulation Induced Cell Death in Regulatory and Conventional T Cells
Abstract
The adaptive immune response relies on a multitude of factors to maintain homeostasis. T cell homeostasis is interconnected with the number of T cells responding to an antigen and is guided by pre-programmed death pathways critical for self-regulation. Upon antigen stimulation, conventional effector T cell (Tcon) proliferation is constrained by both forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) and restimulation-induced cell death (RICD). Restimulation-induced cell death (RICD) is an apoptotic program triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Tregs are considered key mediators of immune homeostasis, mainly by their ability to suppress the activation and function of other T cells. Although 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) lack the adaptor molecule SLAM-associated protein (SAP), and are resistant to RICD due to reduced TCR signal strength upon restimulation. Here we demonstrate that FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter, which ensures low SAP levels in order to reduce TCR signal strength upon restimulation. Our findings illuminate the SAP-dependent mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 04, 2019
- Accession Number
- AD1128120
Entities
People
- Kelsey Voss
Organizations
- Uniformed Services University of the Health Sciences