Regulation of positive and negative selection and TCR signaling during thymic T cell development by capicua
Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, dysregulation of the thymic selection process often leads to autoimmunity. Here, we show that Capicua (CIC), a transcriptional repressor that suppresses autoimmunity, controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impairs both positive and negative selection of thymocytes. CIC deficiency attenuated TCR signaling in CD4+CD8+ double-positive (DP) cells, as evidenced by a decrease in CD5 and phospho-ERK levels and calcium flux. We identified Spry4, Dusp4, Dusp6, and Spred1 as CIC target genes that could inhibit TCR signaling in DP cells. Furthermore, impaired positive selection and TCR signaling were partially rescued in Cic and Spry4 double mutant mice. Our findings indicate that CIC is a transcription factor required for thymic T cell development and suggests that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.
The Gene Expression Omnibus (GEO) accession number for the RNA sequencing data of DP thymocytes reported in this paper is GSE173909. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, 5, 6, and 7.
RNA Sequencing Analysis of Gene Expression Profiles in WT and CIC-deficient DP ThymocytesNCBI Gene Expression Omnibus, GSE173909.
Article and author information
Samsung Science and Technology Foundation (SSTF-BA1502-14)
- Yoontae Lee
National Research Foundation of Korea (NRF-2021R1A2C3004006)
- Yoontae Lee
National Research Foundation of Korea (NRF-2017R1A5A1015366)
- Yoontae Lee
National Research Foundation of Korea (NRF-2017H1A2A1042705)
- Hyebeen Hong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee of Pohang University of Science and Technology (POSTECH-2019-0081). All experiments were carried out in accordance with the approved guidelines. Mouse sacrifice was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
- Juan Carlos Zúñiga-Pflücker, University of Toronto, Sunnybrook Research Institute, Canada
- Received: June 29, 2021
- Preprint posted: July 12, 2021 (view preprint)
- Accepted: December 10, 2021
- Accepted Manuscript published: December 13, 2021 (version 1)
- Version of Record published: December 23, 2021 (version 2)
© 2021, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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