Abstract
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.
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Acknowledgements
We thank Michael Lenardo for generously providing access to anonymous healthy donor buffy coat samples from the NIH Blood Bank. We also thank Robert Kortum, Brian Schaefer, Chou-Zen Giam, Edward Mitre, and Jason Lees for helpful discussions. We thank Kateryna Lund and Kheem Bhist for flow cytometry assistance and support. This work was funded by grants from the National Institutes of Health (1R01GM105821) and Uniformed Services University.
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K.V. and A.L.S. conceptualized the project. K.V. designed and conducted the experiments, analyzed the results, graphed and visualized the data, and wrote the paper. N.M.L., C.L.D., A.R.S. and G.S. conducted the RNA-seq experiments and analyses. C.L., C.R.L., B.D., S.A. and B.M.B. assisted with various experiments. A.L.S. and C.L.D. reviewed and edited the paper and supervised the project.
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Voss, K., Lake, C., Luthers, C.R. et al. FOXP3 protects conventional human T cells from premature restimulation-induced cell death. Cell Mol Immunol 18, 194–205 (2021). https://doi.org/10.1038/s41423-019-0316-z
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DOI: https://doi.org/10.1038/s41423-019-0316-z