Department of Clinical Laboratory and Hematology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
Department of Clinical Laboratory and Hematology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
Immunol Lett. 2018 Jun;198:17-25. doi: 10.1016/j.imlet.2018.03.010. Epub 2018 Mar 27.
Our previous study demonstrated that beta 2-glycoprotein I (β2GPI) stimulation promotes bone marrow derived dendritic cells (BMDCs) maturation and T cell proliferation in a Toll-like receptor 4 (TLR4) dependent manner. However, β2GPI induced T cell differentiation and the role of TLR4 in this process have rarely been reported. In the present study, we focused on the differentiation of splenic T cells in β2GPI immunized Balb/c, C3H/HeN and C3H/HeJ mice. According to our results, Th2 dominated differentiation was observed in β2GPI immunized Balb/c and C3H/HeN mice than in those treated with normal saline (NS), namely the up-regulated levels of Th2 markers GATA3 and IL-4 (p < 0.05). Meanwhile, reduced Th1 markers T-bet and IFN-γ, and Treg marker Foxp3 were observed in β2GPI immunized mice (p < 0.05). C3H/HeJ mice have the same gene background with C3H/HeN mice except a functional mutant in TLR4 gene. However, the described Th2 differentiation was not detected in these TLR4 deficient mice, indicating the importance of TLR4 in immune response against β2GPI. In addition, we found that β2GPI-induced Th2 differentiation could be strengthened by cytokines secreted by dendritic cells (DCs) and DCs-T cells interaction. However, DCs-T cells contact was indispensable during this process because of its unique role in suppressing Th1 function. Furthermore, this Th2 biased differentiation pattern was more noticeable in mice received 4 times β2GPI immunization than those received 2 times, suggesting the amplifying effects of anti-β2GPI Ab on β2GPI induced Th2 response. These findings may partly explain the immune imbalance in APS patient through the view angle of T cell differentiation and anti-β2GPI antibody production.
我们之前的研究表明，β2 糖蛋白 I（β2GPI）刺激以 Toll 样受体 4（TLR4）依赖性方式促进骨髓来源的树突状细胞（BMDCs）成熟和 T 细胞增殖。然而，β2GPI 诱导 T 细胞分化，TLR4 在这一过程中的作用很少有报道。在本研究中，我们专注于β2GPI 免疫 Balb/c、C3H/HeN 和 C3H/HeJ 小鼠脾 T 细胞的分化。根据我们的结果，与生理盐水（NS）处理组相比，β2GPI 免疫的 Balb/c 和 C3H/HeN 小鼠观察到 Th2 优势分化，即 Th2 标志物 GATA3 和 IL-4 的上调水平（p<0.05）。同时，β2GPI 免疫的小鼠中观察到 Th1 标志物 T-bet 和 IFN-γ以及 Treg 标志物 Foxp3 减少（p<0.05）。C3H/HeJ 小鼠与 C3H/HeN 小鼠具有相同的基因背景，除了 TLR4 基因的功能性突变。然而，在这些 TLR4 缺陷小鼠中没有检测到描述的 Th2 分化，表明 TLR4 在针对β2GPI 的免疫反应中的重要性。此外，我们发现树突状细胞（DCs）分泌的细胞因子和 DCs-T 细胞相互作用可增强β2GPI 诱导的 Th2 分化。然而，在这个过程中，DCs-T 细胞接触是必不可少的，因为它在抑制 Th1 功能方面具有独特的作用。此外，与接受 2 次β2GPI 免疫的小鼠相比，接受 4 次β2GPI 免疫的小鼠中这种 Th2 偏向性分化模式更为明显，这表明抗-β2GPI Ab 对β2GPI 诱导的 Th2 反应具有放大作用。这些发现可能从 T 细胞分化和抗-β2GPI 抗体产生的角度部分解释 APS 患者的免疫失衡。
