Iglesias Marcos, Augustin Juan Jesús, Alvarez Pilar, Santiuste Inés, Postigo Jorge, Merino Jesús, Merino Ramón
Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain.
Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria, Santander, Spain.
PLoS One. 2016 Jul 19;11(7):e0159714. doi: 10.1371/journal.pone.0159714. eCollection 2016.
The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the T-cell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4+ cells after in vitro TCR stimulation. In addition, the in vitro and in vivo TH17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4+ cells and their differentiation into pathogenic proinflammatory TH17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases.
通过BCL2家族成员的表达失调来抑制T细胞中的凋亡性细胞死亡，这与预防不同自身免疫性疾病的发生有关。然而，人们提出了多种机制来解释这种保护作用。本研究的目的是探讨抗凋亡BCL2家族成员BCL2A1在T细胞中过表达对胶原诱导性关节炎发展的影响，该成员对细胞周期进程无影响。我们的结果表明，这些转基因小鼠的关节炎发展得到了缓解。这种保护作用与调节性T细胞的抑制活性无关，但与体外TCR刺激后CD4+细胞中p38丝裂原活化蛋白激酶的激活缺陷有关。此外，BCL2A1转基因小鼠的体外和体内TH17分化均受损。综上所述，我们在此证明了BCL2A1在控制CD4+细胞的激活及其分化为致病性促炎TH17细胞方面具有此前未知的作用，并将BCL2A1确定为控制自身免疫性/炎症性疾病的潜在靶点。
