흉선 T 세포 발달 및 T 세포 수용체 신호 전달에서 Capicua의 조절 역할에 관한 연구

Abstract

T cells recognize specific antigens with the T cell receptor (TCR), which is produced by a random rearrangement of T cell receptor (TCR) genes. To reduce the risk of autoimmunity, some T cells with TCRs specific to self-antigens must be removed, and this is accomplished through several mechanisms, including central tolerance and peripheral tolerance. Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, the dysregulation of the thymic selection process often leads to autoimmunity. Capicua (CIC) is a transcriptional repressor that regulates the receptor tyrosine kinase (RTK) signaling pathway in Drosophila and mammals. CIC recognizes specific octameric DNA sequences (5ʹ-T(G/C)AATG(A/G)(A/G)-3ʹ) within its target gene promoter regions and represses their expression. In mammals, CIC plays multiple roles in several diseases, including several types of cancer. Recent studies using hematopoietic lineage cell-specific and T cell-specific Cic-null mice suggested that CIC suppresses autoimmunity. Here, I show that CIC controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impaired 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, phospho-ERK levels, and calcium flux. I 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. My findings indicate that CIC is a transcription factor required for thymic T cell development and suggest that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.