Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages
Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages
复制标题
DOI：
10.1210/en.2019-00025
复制
发表时间：
2019-07-01
期刊：
影响因子：
4.8
通讯作者：
Nelson, Erik R.
中科院分区：
文献类型：
--
作者：
Shahoei, Sayyed Hamed;Kim, Young-Chae;Nelson, Erik R.
小异源二聚体伴侣（SHP）参与抑制肝胆汁酸合成胆固醇已被确立。然而，肝外表达的SHP意味着，SHP可能有调节功能以外的肝脏。在这里，我们发现，SHP mRNA的表达是高的小鼠骨髓细胞，这表明在巨噬细胞内的生理作用。事实上，SHP在巨噬细胞中的表达降低了核因子κ B的转录活性和核定位，而SHP的下调具有相反的效果。与巨噬细胞-T细胞串扰相关的基因的表达通过SHP的过表达或下调而改变。有趣的是，巨噬细胞中SHP表达的增加导致T细胞扩增减少，这是T细胞活化的标志，而SHP的敲低导致扩增增加。对扩增的T细胞的分析揭示了效应T细胞和调节T细胞（T-T细胞）之间的二分偏斜，其中SHP过表达降低T-T细胞，而SHP的下调增加其扩增。通过过继转移证实了扩增的T-T细胞是抑制性的。IL-2和TGF-β，已知的T-reg分化诱导剂，被发现由SHP调节。此外，在IL-2的启动子区域的SHP占用增加后，巨噬细胞与脂多糖的挑战。IL-2和TGF-β的中和抗体抑制了由SHP下调介导的T-CRP的扩增。这项研究表明，巨噬细胞内SHP的表达和活性可以改变T细胞的命运，并确定SHP作为自身免疫性疾病或实体癌的潜在治疗靶点。
The involvement of small heterodimer partner (SHP) in the inhibition of hepatic bile acid synthesis from cholesterol has been established. However, extrahepatic expression of SHP implies that SHP may have regulatory functions other than those in the liver. Here, we find that SHP mRNA expression is high in murine bone marrow cells, suggesting a physiological role within macrophages. Indeed, expression of SHP in macrophages decreases the transcriptional activity and nuclear localization of nuclear factor kappa B, whereas downregulation of SHP has the opposite effects. Expression of genes associated with macrophage-T cell crosstalk were altered by overexpression or downregulation of SHP. Intriguingly, increasing SHP expression in macrophages resulted in decreased T cell expansion, a hallmark of T cell activation, whereas knockdown of SHP resulted in increased expansion. Analyses of the expanded T cells revealed a dichotomous skewing between effector T cells and regulatory T cells (T-regs), with SHP overexpression reducing Tregs and downregulation of SHP increasing their expansion. The expanded T-regs were confirmed to be suppressive via adoptive transfers. IL-2 and TGF-beta, known inducers of T-reg differentiation, were found to be regulated by SHP. Furthermore, SHP occupancy at the promoter region of IL-2 was increased after macrophages were challenged with lipopolysaccharide. Neutralizing antibodies to IL-2 and TGF-b inhibited the expansion of T-regs mediated by downregulation of SHP. This study demonstrates that expression and activity of SHP within macrophages can alter T cell fate and identifies SHP as a potential therapeutic target for autoimmune diseases or solid cancers.