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

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44(hi)CD62L(lo) 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 (Cic(f/f);Vav1-Cre) and T cell-specific Cic-null (Cic(f/f);Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4(+) T cells were more apparent in Cic(f/f);Vav1-Cre mice than in Cic(f/f);Cd4-Cre mice. Cic(f/f);Vav1-Cre CD4(+) T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cic(f/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 Cic(f/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 Cic(f/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.