Abstract：
EFHD2 (EF-hand domain family, member D2) has been identified as a calcium-binding protein with immunomodulatory effects. In this study, we characterized the phenotype of Efhd2-deficient mice in sepsis and examined the biological functions of EFHD2 in peripheral T cell activation and T helper (Th) cell differentiation. Increased levels of EFHD2 expression accompanied peripheral CD4+ T cell activation in the early stages of sepsis. Transcriptomic analysis indicated that immune response activation was impaired in Efhd2-deficient CD4+ T cells. Further, Efhd2-deficient CD4+ T cells isolated from the spleen of septic mice showed impaired T cell receptor (TCR)-induced Th differentiation, especially Th1 and Th17 differentiation. In vitro data also showed that Efhd2-deficient CD4+ T cells exhibit impaired Th1 and Th17 differentiation. In the CD4+ T cells and macrophages co-culture model for antigen presentation, the deficiency of Efhd2 in CD4+ T cells resulted in impaired formation of immunological synapses. In addition, Efhd2-deficient CD4+ T cells exhibited reduced levels of phospho-LCK and phospho-ZAP70, and downstream transcription factors including Nfat, Nfκb and Nur77 following TCR engagement. In summary, EFHD2 may promote TCR-mediated T cell activation subsequent Th1 and Th17 differentiation in the early stages of sepsis by regulating the intensity of TCR complex formation.
摘要：
EFHD2(EF-handdomainfamily,成员D2）已被鉴定为具有免疫调节作用的钙结合蛋白。在这项研究中,我们对Efhd2缺陷型小鼠在脓毒症中的表型进行了表征,并检测了EFHD2在外周T细胞活化和T辅助(Th)细胞分化中的生物学功能.在脓毒症的早期阶段，EFHD2表达水平的增加伴随着外周CD4+T细胞的活化。转录组分析表明,在Efhd2缺陷型CD4+T细胞中,免疫应答激活受损。Further,从脓毒症小鼠脾脏中分离的Efhd2缺陷型CD4+T细胞显示T细胞受体（TCR）诱导的Th分化受损，特别是Th1和Th17的分化。体外数据还显示Efhd2缺陷型CD4+T细胞表现出受损的Th1和Th17分化。在用于抗原呈递的CD4+T细胞和巨噬细胞共培养模型中，CD4+T细胞中Efhd2的缺乏导致免疫突触的形成受损。此外,Efhd2缺陷型CD4+T细胞的磷酸-LCK和磷酸-ZAP70水平降低，下游转录因子包括Nfat，TCR参与后的NFκb和Nur77。总之,EFHD2可能通过调节TCR复合物形成的强度促进脓毒症早期Th1和Th17分化后TCR介导的T细胞活化。
