Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Institute of Immunobiology, Cantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland.
J Exp Med. 2014 Dec 15;211(13):2507-17. doi: 10.1084/jem.20140137. Epub 2014 Dec 8.
Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell-DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4(+) T cells. During inflammation, weak tetramer-binding TP-deficient CD4(+) T cells were preferentially expanded compared with TP-proficient CD4(+) T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4(+) T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4(+) T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4(+) T cell-DC interactions by TXA2-TP signaling improves the overall quality of adaptive immune responses.
树突状细胞 (DC) 与 T 细胞之间的相互作用控制着激活与耐受诱导之间的决策。血栓烷 A2 (TXA2) 及其受体 TP 被认为通过控制 T 细胞-DC 相互作用来调节适应性免疫反应。在这里，我们表明这种控制是通过选择性减少低亲和力 CD4(+) T 细胞的扩增来实现的。在炎症期间，与 TP 功能正常的 CD4(+) T 细胞相比，弱四聚体结合的 TP 缺陷型 CD4(+) T 细胞优先扩增。通过对反应性外周淋巴结 (PLN) 中细胞相互作用的活体成像，我们发现 TXA2 导致低亲和力但不是高亲和力的 DC 和 CD4(+) T 细胞之间的相互作用被破坏。TP 的缺乏与刺激的 CD4(+) T 细胞上激活标志物的更高表达以及滤泡辅助性 T 细胞 (TFH) 的增加积累相关，这与低亲和力 IgG 反应的增加相关。总之，我们的数据表明，TXA2-TP 信号对弱 CD4(+) T 细胞-DC 相互作用的持续抑制可改善适应性免疫反应的整体质量。
