Quantitative Proteomics Identifies TCF1 as a Negative Regulator of Foxp3 Expression in Conventional T Cells

• Main Authors: Michael Delacher, Melanie M. Barra, Yonatan Herzig, Katrin Eichelbaum, Mahmoud-Reza Rafiee, David M. Richards, Ulrike Träger, Ann-Cathrin Hofer, Alexander Kazakov, Kathrin L. Braband, Marina Gonzalez, Lukas Wöhrl, Kathrin Schambeck, Charles D. Imbusch, Jakub Abramson, Jeroen Krijgsveld, Markus Feuerer
• Format: Article
• Language: English
• Published: Elsevier 2020-05-01
• Series: iScience
• Subjects: Molecular Biology; Molecular Mechanism of Gene Regulation; Immunology; Proteomics
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220303126

Summary: Regulatory T cells are important regulators of the immune system and have versatile functions for the homeostasis and repair of tissues. They express the forkhead box transcription factor Foxp3 as a lineage-defining protein. Negative regulators of Foxp3 expression are not well understood. Here, we generated double-stranded DNA probes complementary to the Foxp3 promoter sequence and performed a pull-down with nuclear protein in vitro, followed by elution of bound proteins and quantitative mass spectrometry. Of the Foxp3-promoter-binding transcription factors identified with this approach, one was T cell factor 1 (TCF1). Using viral over-expression, we identified TCF1 as a repressor of Foxp3 expression. In TCF1-deficient animals, increased levels of Foxp3intermediateCD25negative T cells were identified. CRISPR-Cas9 knockout studies in primary human and mouse conventional CD4 T (Tconv) cells revealed that TCF1 protects Tconv cells from inadvertent Foxp3 expression. Our data implicate a role of TCF1 in suppressing Foxp3 expression in activated T cells.