Nevers Tania, Salvador Ane M, Velazquez Francisco, Ngwenyama Njabulo, Carrillo-Salinas Francisco J, Aronovitz Mark, Blanton Robert M, Alcaide Pilar
Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA.
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
J Exp Med. 2017 Nov 6;214(11):3311-3329. doi: 10.1084/jem.20161791. Epub 2017 Oct 2.
Despite emerging data indicating a role for T cells in profibrotic cardiac repair and healing after ischemia, little is known about whether T cells directly impact cardiac fibroblasts (CFBs) to promote cardiac fibrosis (CF) in nonischemic heart failure (HF). Recently, we reported increased T cell infiltration in the fibrotic myocardium of nonischemic HF patients, as well as the protection from CF and HF in TCR-α mice. Here, we report that T cells activated in such a context are mainly IFN-γ, adhere to CFB, and induce their transition into myofibroblasts. Th1 effector cells selectively drive CF both in vitro and in vivo, whereas adoptive transfer of Th1 cells, opposite to activated IFN-γ Th cells, partially reconstituted CF and HF in TCR-α recipient mice. Mechanistically, Th1 cells use integrin α4 to adhere to and induce TGF-β in CFB in an IFN-γ-dependent manner. Our findings identify a previously unrecognized role for Th1 cells as integrators of perivascular CF and cardiac dysfunction in nonischemic HF.
尽管新出现的数据表明T细胞在缺血后促纤维化的心脏修复和愈合中发挥作用，但对于T细胞是否直接影响心脏成纤维细胞（CFB）以促进非缺血性心力衰竭（HF）中的心脏纤维化（CF），人们了解甚少。最近，我们报道了非缺血性HF患者纤维化心肌中T细胞浸润增加，以及TCR-α小鼠对CF和HF具有保护作用。在此，我们报告在这种情况下被激活的T细胞主要是IFN-γ，它黏附于CFB并诱导其转变为肌成纤维细胞。Th1效应细胞在体外和体内均选择性地驱动CF，而与活化的IFN-γ Th细胞相反，Th1细胞的过继转移部分重建了TCR-α受体小鼠的CF和HF。从机制上讲，Th1细胞利用整合素α4以IFN-γ依赖的方式黏附于CFB并诱导其产生TGF-β。我们的研究结果确定了Th1细胞在非缺血性HF中作为血管周围CF和心脏功能障碍整合者的一个先前未被认识的作用。
