Kaczmarek Julita, Homsi Yahya, van Üüm Jan, Metzger Christina, Knolle Percy A, Kolanus Waldemar, Lang Thorsten, Diehl Linda
Institute of Molecular Medicine at the LIMES Institute, University of Bonn, Bonn, Germany.
Department of Membrane Biochemistry at the LIMES Institute, University of Bonn, Bonn, Germany.
PLoS One. 2014 Jun 12;9(6):e99574. doi: 10.1371/journal.pone.0099574. eCollection 2014.
The initiation of adaptive immunity requires cell-to-cell contact between T cells and antigen-presenting cells. Together with immediate TCR signal transduction, the formation of an immune synapse (IS) is one of the earliest events detected during T cell activation. Here, we show that interaction of liver sinusoidal endothelial cells (LSEC) with naive CD8 T cells, which induces CD8 T cells without immediate effector function, is characterized by a multi-focal type IS. The co-inhibitory molecule B7H1, which is pivotal for the development of non-responsive LSEC-primed T cells, did not alter IS structure or TCRβ/CD11a cluster size or density, indicating that IS form does not determine the outcome of LSEC-mediated T cell activation. Instead, PD-1 signaling during CD8 T cell priming by LSEC repressed IL-2 production as well as sustained CD25 expression. When acting during the first 24 h of LSEC/CD8 T cell interaction, CD28 co-stimulation inhibited the induction of non-responsive LSEC-primed T cells. However, after more than 36 h of PD-1 signaling, CD28 co-stimulation failed to rescue effector function in LSEC-primed T cells. Together, these data show that during LSEC-mediated T cell priming, integration of co-inhibitory PD-1 signaling over time turns on a program for CD8 T cell development, that cannot be overturned by co-stimulatory signals.
适应性免疫的启动需要T细胞与抗原呈递细胞之间的细胞间接触。与即时的TCR信号转导一起，免疫突触（IS）的形成是T细胞活化过程中最早检测到的事件之一。在这里，我们表明肝窦内皮细胞（LSEC）与初始CD8 T细胞的相互作用，诱导出无即时效应功能的CD8 T细胞，其特征是多灶性免疫突触。共抑制分子B7H1对无反应性的LSEC启动的T细胞的发育至关重要，但它并未改变免疫突触结构或TCRβ/CD11a簇的大小或密度，这表明免疫突触的形式并不能决定LSEC介导的T细胞活化的结果。相反，LSEC启动CD8 T细胞过程中的PD-1信号传导抑制了IL-2的产生以及CD25的持续表达。当在LSEC/CD8 T细胞相互作用的最初24小时内起作用时，CD28共刺激抑制了无反应性的LSEC启动的T细胞的诱导。然而，在PD-1信号传导超过36小时后，CD28共刺激未能挽救LSEC启动的T细胞的效应功能。总之，这些数据表明，在LSEC介导的T细胞启动过程中，共抑制性PD-1信号随时间的整合开启了一个CD8 T细胞发育程序，该程序不能被共刺激信号所逆转。
