Schambach Felix, Schupp Michael, Lazar Mitchell A, Reiner Steven L
Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eur J Immunol. 2007 Sep;37(9):2396-9. doi: 10.1002/eji.200737621.
Autoimmunity is thought to reflect an imbalance between regulatory T helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper (Th17) cells. Induction of both adaptive Treg and Th17 cells requires signalling from TGF-beta. We now show that, in the context of TGF-beta signalling, all-trans retinoic acid (ATRA) leads to increased induction of CD4(+) T cells expressing the Treg specification factor forkhead box protein P3 (FoxP3) and decreased frequency of cells expressing IL-17, even in the presence of IL-6. Using a specific agonist and antagonist, as well as retroviral over-expression, we also provide evidence that the effects of ATRA are likely to be at least partially mediated by the nuclear retinoic acid receptor-alpha (RARalpha). These findings indicate that signalling through a specific nuclear retinoic acid receptor can favour the decision to adopt the Treg fate at the expense of Th17 fate. Specific agonists of RARalpha could, therefore, be considered candidates for the treatment of autoimmunity.
自身免疫被认为反映了调节性辅助性T淋巴细胞（Treg）与致病性、分泌白细胞介素-17的辅助性T细胞（Th17）之间的失衡。适应性Treg和Th17细胞的诱导都需要转化生长因子-β（TGF-β）发出信号。我们现在表明，在TGF-β信号传导的背景下，全反式维甲酸（ATRA）会导致表达Treg特异性因子叉头框蛋白P3（FoxP3）的CD4（+）T细胞诱导增加，即使在存在白细胞介素-6的情况下，表达白细胞介素-17的细胞频率也会降低。使用特异性激动剂和拮抗剂，以及逆转录病毒过表达，我们还提供了证据表明，ATRA的作用可能至少部分由核维甲酸受体-α（RARα）介导。这些发现表明，通过特定核维甲酸受体发出的信号可以有利于做出采用Treg命运而非Th17命运的决定。因此，RARα的特异性激动剂可被视为自身免疫治疗的候选药物。
