Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells
Year: 2025
Type: article
Abstract: Regulatory T (T reg ) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the T reg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated T reg cells, Foxp3 loss in mature T reg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature T reg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of T reg cell transcriptome and fitness. Furthermore, tumoral T reg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for T reg transcriptional and functional programs.
Source: Nature Immunology
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Health and Human Services, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Memorial Sloan-Kettering Cancer Center, Ludwig Institute for Cancer Research, Cycle for Survival, National Institutes of Health, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: G1075614049, G2051006376, G2308033977, G289723095, G342219358, G4102770861, G4168869313, G4367980300, G4621852861, Self Peptides Bound to MHC Class II In T Cell Selection, G5109122429, G546047228, G5835552564, G7136384868, G7536249055, G9000003249, G9000073387, G9000098862, Cancer Center Support Grant, Self-Peptides Bound to MHC Class II in T Cell Selection
OpenAlex ID: W4414947359