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Deletion Timing of Cic Alleles during Hematopoiesis Determines the Degree of Peripheral CD4+ T Cell Activation and Proliferation

  • Guk-Yeol Park (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Gil-Woo Lee (Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology (POSTECH)) ;
  • Soeun Kim (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Hyebeen Hong (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Jong Seok Park (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Jae-Ho Cho (Medical Research Center for Combinatorial Tumor Immunotherapy, Immunotherapy Innovation Center, Department of Microbiology and Immunology, Chonnam National University Medical School, Hwasun Hospital) ;
  • Yoontae Lee (Department of Life Sciences, Pohang University of Science and Technology (POSTECH))
  • Received : 2020.07.31
  • Accepted : 2020.10.08
  • Published : 2020.10.31
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Abstract

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44hiCD62Llo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4+CD8+ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4+ T cell activation and proliferation between whole immune cell-specific Cic-null (Cicf/f;Vav1-Cre) and T cell-specific Cic-null (Cicf/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4+ T cells were more apparent in Cicf/f;Vav1-Cre mice than in Cicf/f;Cd4-Cre mice. Cicf/f;Vav1-Cre CD4+ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cicf/f;Cd4-Cre CD4+ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cicf/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4+ T cells than did mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability.

Keywords

Acknowledgement

We thank the Lee lab members for helpful discussions and comments on this study. This work was supported by grants from the Samsung Science and Technology Foundation under project number SSTF-BA1502-14 and the National Research Foundation (NRF) of Korea (2017R1A5A1015366 and 2018R1A2B2004416 for YL; 2018R1A5A2024181 and 2020M3A9G3080281 for JHC). GYP, HH, SK, and JSP were supported by the BK21 Program.

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