CRISPR screen in regulatory T cells reveals modulators of Foxp3

Jessica T. Cortez, Elena Montauti, Eric Shifrut, Jovylyn Gatchalian, Yusi Zhang, Oren Shaked, Yuanming Xu, Theodore L. Roth, Dimitre R. Simeonov, Yana Zhang, Siqi Chen, Zhongmei Li, Jonathan M. Woo, Josephine Ho, Ian A. Vogel, Grace Y. Prator, Bin Zhang, Youjin Lee, Zhaolin Sun, Igal Ifergan, Frédéric Van Gool, Diana C. Hargreaves, Jeffrey A. Bluestone, Alexander Marson () and Deyu Fang ()
Additional contact information
Jessica T. Cortez: University of California
Elena Montauti: Northwestern University Feinberg School of Medicine
Eric Shifrut: University of California
Jovylyn Gatchalian: Salk Institute for Biological Studies
Yusi Zhang: Northwestern University Feinberg School of Medicine
Oren Shaked: University of California
Yuanming Xu: Northwestern University Feinberg School of Medicine
Theodore L. Roth: University of California
Dimitre R. Simeonov: University of California
Yana Zhang: Northwestern University Feinberg School of Medicine
Siqi Chen: Northwestern University Feinberg School of Medicine
Zhongmei Li: University of California
Jonathan M. Woo: University of California
Josephine Ho: Salk Institute for Biological Studies
Ian A. Vogel: University of California
Grace Y. Prator: University of California
Bin Zhang: Northwestern University Feinberg School of Medicine
Youjin Lee: University of California
Zhaolin Sun: Dalian Medical University School of Pharmacy
Igal Ifergan: Northwestern University Feinberg School of Medicine
Frédéric Van Gool: University of California
Diana C. Hargreaves: Salk Institute for Biological Studies
Jeffrey A. Bluestone: University of California
Alexander Marson: University of California
Deyu Fang: Northwestern University Feinberg School of Medicine

Nature, 2020, vol. 582, issue 7812, 416-420

Abstract: Abstract Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties2, can promote autoimmunity and/or facilitate more effective tumour immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Treg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

Date: 2020
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DOI: 10.1038/s41586-020-2246-4

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