Vitiello Laura, Ferraro Elisabetta, De Simone Salvatore, Gatta Lucia, Feraco Alessandra, Racioppi Luigi, Rosano Giuseppe
Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, 00166, Rome, Italy.
Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, 00166, Rome, Italy.
Int J Cardiol. 2016 Dec 1;224:206-212. doi: 10.1016/j.ijcard.2016.09.007. Epub 2016 Sep 12.
Naive T lymphocytes recirculate through the body, traveling from secondary lymphoid organs through tissues and via lymphatic vessels and peripheral blood into other secondary lymphoid organs and into the bone marrow. In these tissues, lymphocytes are exposed to the chemokine CXCL12 which is abundantly produced in bone marrow and in lymph nodes by stromal cells. CXCL12 is known to drive lymphocytes chemotaxis and, in cells types such as stem cells, an antiapopototic effect has been described.
Here we analyzed the effect of CXCL12 exposure on naïve CD4+ T lymphocytes purified from peripheral blood by immunomagnetic negative isolation and cultured in a nutrient poor medium. We also studied, mainly by western blot analysis, the signaling pathways involved in CXCL12 action on naïve CD4+ T lymphocytes.
We found that CXCL12-exposed cells survived longer than untreated ones and this prolonged lifespan was specific for resting naïve lymphocytes, while in vitro activated lymphoblasts died rapidly despite CXCL12 treatment. We demonstrated that the increased percentage of living cells observed upon CXCL12 administration was not due to induction of proliferation but to a prosurvival effect of this chemokine. Moreover, our data suggest that this prosurvival effect on naïve CD4+ T lymphocytes might likely be mediated by PKA-dependent CREB activation and consequent increased expression of the antiapoptotic factors Bcl2 and BclXl.
This newly reported activity of CXCL12 might contribute to the maintenance of the naïve T lymphocytes pool in vivo, which is needed to ensure a proper immune response to new antigens.
初始T淋巴细胞在体内循环，从二级淋巴器官经组织、淋巴管和外周血进入其他二级淋巴器官及骨髓。在这些组织中，淋巴细胞会接触到趋化因子CXCL12，它由骨髓和淋巴结中的基质细胞大量产生。已知CXCL12可驱动淋巴细胞趋化，并且在干细胞等细胞类型中，已描述了其抗凋亡作用。
在此，我们分析了CXCL12作用于通过免疫磁珠阴性分选从外周血中纯化并在营养匮乏培养基中培养的初始CD4+ T淋巴细胞的效果。我们还主要通过蛋白质印迹分析研究了CXCL12作用于初始CD4+ T淋巴细胞所涉及的信号通路。
我们发现，接触CXCL12的细胞比未处理的细胞存活时间更长，这种延长的寿命对静止的初始淋巴细胞具有特异性，而体外活化的淋巴母细胞尽管接受了CXCL12处理仍迅速死亡。我们证明，给予CXCL12后观察到的活细胞百分比增加并非由于诱导增殖，而是由于该趋化因子的促存活作用。此外，我们的数据表明，这种对初始CD4+ T淋巴细胞的促存活作用可能由PKA依赖的CREB激活以及随后抗凋亡因子Bcl2和BclXl表达增加介导。
CXCL12的这种新报道的活性可能有助于维持体内初始T淋巴细胞库，这对于确保对新抗原产生适当的免疫反应是必要的。
