TRIM28 Expression on Dendritic Cells Prevents Excessive T Cell Priming by Silencing Endogenous Retrovirus
TRIM28 Expression on Dendritic Cells Prevents Excessive T Cell Priming by Silencing Endogenous Retrovirus
复制标题
DOI：
10.4049/jimmunol.2001003
复制
发表时间：
2021-04-01
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Chikuma, Shunsuke;Yamanaka, Soichiro;Yoshimura, Akihiko
获得性免疫反应是由树突状细胞（dendritic cells，DC）启动的，其将Ag呈递给少数幼稚Ag特异性T细胞。DCs中基因表达的失调可能会改变对免疫缺陷和/或自身免疫性疾病的免疫应答的结果。TRIM 28是一种通过异染色质介导基因沉默的核蛋白，其表达在老年小鼠的DC中减少，表明基因调控的改变。在DC中特异性缺乏TRIM 28的小鼠显示脾脏中DC群体增加和T细胞向炎性效应T细胞的引发增强，导致实验性自身免疫性脑脊髓炎的加速和恶化。发现TRIM 28缺陷型DC异位转录内源性逆转录病毒（ERV）元件。联合全基因组分析显示，在TRIM 28缺陷型DC中，抑制性组蛋白标记H3 K9 me 3转录的ERV元件和与炎症相关的去抑制宿主基因之间存在强烈的共定位。这表明ERV元件的TRIM 28占据严重抑制基因组上近端炎性基因的表达。我们提出，通过TRIM 28抑制性组蛋白修饰的基因沉默在维持DC中精确基因调控的完整性中起作用，这防止了异常T细胞引发炎症效应T细胞。
Acquired immune reaction is initiated by dendritic cells (DCs), which present Ags to a few naive Ag-specific T cells. Deregulation of gene expression in DCs may alter the outcome of the immune response toward immunodeficiency and/or autoimmune diseases. Expression of TRIM28, a nuclear protein that mediates gene silencing through heterochromatin, decreased in DCs from old mice, suggesting alteration of gene regulation. Mice specifically lacking TRIM28 in DCs show increased DC population in the spleen and enhanced T cell priming toward inflammatory effector T cells, leading to acceleration and exacerbation in experimental autoimmune encephalomyelitis. TRIM28-deficient DCs were found to ectopically transcribe endogenous retrovirus (ERV) elements. Combined genome-wide analysis revealed a strong colocalization among the decreased repressive histone mark H3K9me3-transcribed ERV elements and the derepressed host genes that were related to inflammation in TRIM28-deficient DCs. This suggests that TRIM28 occupancy of ERV elements critically represses expression of proximal inflammatory genes on the genome. We propose that gene silencing through repressive histone modification by TRIM28 plays a role in maintaining the integrity of precise gene regulation in DCs, which prevents aberrant T cell priming to inflammatory effector T cells.