Abstract
High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null TFH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in TFH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC–ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates TFH cell development and autoimmunity.
Highlights
High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity
The proportion of naıve and TefFfeRcatonrd/mGeCmBorcyelclselwlsafsoarlsbootchomCpDa4raþbleanbdetwCeDe8nþCiscuþb/sþetsF,oTxpF3H, YFP-Cre (WT) and Cicf/fFoxp3-YFP-Cre mice (Supplementary Fig. 11d–f). These results suggest that CIC deficiency in FOXP3 þ FpTOrreoSgXmincPoce3etlleþs tfdhoTorermeesgFancOtieooXltlnsPc.3oafuþsCeDTd4reeþfgecCcteDslli2-n5spÀdeecFviOfielcXopPCm3iþcendtTe-alcneetdlilofnpuonpdcutidiloantniooontf in spleen (Supplementary Fig. 11c), we examined expression of FOXP3 in conventional CD4 þ T cells from were comparable between Cicf/f (WT) and Cicf/fCd4Cre mice
Our findings demonstrate that CIC is a key transcriptional repressor that maintains peripheral immune homeostasis and restrains TFH cell differentiation, thereby suppressing autoimmunity (Fig. 6g)
Summary
High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. T cells that are targeted to enter B-cell follicles upregulate expression of the transcriptional repressor BCL6 and express an intermediate level of typical TFH molecules (for example, CXCR5, PD-1, ICOS and SAP) at the junction between T-cell and B-cell zone[9,10]. At this stage, developing TFH cells interact with cognate B cells and differentiate into GC TFH cells that express high levels of TFH molecules, such as PD-1 and CXCR5 BCL6 as a master transcription factor for TFH cell differentiation[11,12,13] and BLIMP1 as an antagonist of BCL6
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