Regulation of positive and negative selection and TCR signaling during thymic T cell development by capicua

Abstract

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.

Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8+T cell pathogenicity in non-obese diabetic mice

“…In the pre-positive selection population (DP/TCRβ − CD69 − ), NOD8.3 cells showed significantly higher CD5 expression compared to NOD cells (Figure 5F, upper panel, and Supplementary Figure 3F), implying an enhanced TCR signal perception at the initiation of DP positive selection (52). Consistently, the frequency of CD69 + TCRβ + cells, representing post-positive-selection thymocytes (53), significantly increased in NOD8.3 compared to NOD mice (Figure 5F, lower panel), predisposing to an accelerated accumulation of CD8SP cells (Figure 5D and Supplementary Figure 3C). Additionally, to investigate whether the increased accumulation of CD8SP cell number in NOD8.3 mice is associated with elevated expressions of cytokine receptors crucial for T cell survival in DP stage, we assessed the expression levels of CD122, CD127, CD44 and CD25 in DP thymocytes.…”

Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance

“…Since autophagy promotes positive selection of thymocytes ( 24 ), we evaluated whether the decrease in autophagy in mCat Tg TSCs was sufficient to impair positive selection in this model. To quantify positive selection at the population levels, we measured the frequency of postpositive selection thymocytes among the DP (CD4+ CD8+ double positive) population using CD3 and CD69 as indicators of the postpositive selection subset ( 32 , 33 ). As shown in SI Appendix , Fig.…”

Generation of hematopoietic lineage cell-specific chimeric mice using retrovirus-transduced fetal liver cells

“…The frequency and number of B-1a cells in Bhlhe41 −/− mice are significantly reduced compared to those in wild-type mice ( Kreslavsky et al., 2017 ). Capicua (CIC) is a high mobility group (HMG) box-containing transcriptional repressor that regulates lymphocyte development and differentiation ( Hong et al., 2022 ; Kim et al., 2021 ; Lee, 2020 ; Park et al., 2017 , 2019 , 2020 ). B-cell-specific Cic null ( Cic f/f ;Cd19-Cre ) mice exhibited expansion of the B-1a cell population ( Hong et al., 2022 ).…”