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Studies on the role of Capicua in T cell activation and Treg homeostasis

Title
Studies on the role of Capicua in T cell activation and Treg homeostasis
Authors
박국열
Date Issued
2021
Publisher
포항공과대학교
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). 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. Regulatory T (Treg) cells maintain immune tolerance and homeostasis by suppressing excessive T cell activation. Cicf/f;Cd4-Cre mice exhibited not only autoimmunity with expansion of effector/memory T cells but also increased CD4+FOXP3+ Treg cells, especially CD25-FOXP3+ Tregs. However, the change in the proportion of CD25-FOXP3+ Treg cells was not observed in Treg cell-specific Cic-null (Cicf/f;Foxp3-YFP-Cre) mice. Treg cells in Cicf/f;Cd4-Cre mice showed limited cytokine availability such as decreased expression levels of cytokine receptors and reduced responsiveness to cytokines. In addition, they exhibited higher proliferative capability compared to those in wild-type mice. Detailed analysis demonstrated that increased Tregs in Cicf/f;Cd4-Cre mice have effector phenotypes characterized by CD44hiCD62Llo and low levels of CD25 expression. The mixed wild-type and Cicf/f;Cd4-Cre bone marrow chimeras clearly revealed that these phenotypes were due to T cell-intrinsic loss of CIC. In summary, my studies led to two following conclusions. First, CIC deficiency at the beginning of T cell development endows peripheral CD4+ T cells with enhanced T cell activation and proliferative capability. Second, Cd4-Cre-mediated loss of CIC prior to Treg differentiation contributes to the expansion of CD25-FOXP3+ effector Treg cell population. These results highlight the emerging roles of CIC in T cell activation and maintaining Treg homeostasis.
URI
http://postech.dcollection.net/common/orgView/200000367236
https://oasis.postech.ac.kr/handle/2014.oak/111313
Article Type
Thesis
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