FOXP3 protects conventional human T cells from premature restimulation-induced cell death.

Autor: Voss K; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Lake C; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Luthers CR; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Lott NM; The American Genome Center (TAGC), Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Dorjbal B; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Arjunaraja S; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Bauman BM; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA., Soltis AR; The American Genome Center (TAGC), Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Sukumar G; The American Genome Center (TAGC), Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Dalgard CL; The American Genome Center (TAGC), Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.; Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Snow AL; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, 20817, USA. andrew.snow@usuhs.edu.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2021 Jan; Vol. 18 (1), pp. 194-205. Date of Electronic Publication: 2019 Oct 28.
DOI: 10.1038/s41423-019-0316-z
Abstrakt: The adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3) + -regulatory T cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.
Databáze: MEDLINE
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