Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
J Immunol. 2010 Apr 15;184(8):4107-14. doi: 10.4049/jimmunol.0902580. Epub 2010 Mar 8.
Cross-presentation of soluble Ag on MHC class I molecules to naive CD8 T cells by liver sinusoidal endothelial cells (LSECs) leads to induction of T cell tolerance that requires interaction between coinhibitory B7-H1 on LSECs and programmed cell death-1 on CD8 T cells. In this study, we investigate whether cross-presentation of high as well as low Ag concentrations allowed for LSEC-induced tolerance. Ag concentration directly correlated with the cross-presentation capacity of murine LSECs and thus strength of TCR stimulation. Although LSEC cross-presentation at low-Ag concentrations resulted in tolerance, they induced differentiation into effector T cells (CTL) at high-Ag concentrations. CTL differentiation under these conditions was not caused by increased expression of costimulatory CD80/86 on cross-presenting LSECs but was determined by early IL-2 release from naive CD8 T cells. B7-H1 signals from LSECs and TCR avidity reciprocally controlled early T cell release of IL-2 and CTL differentiation. B7-H1 expression directly correlated with cross-presentation at low- but not high-Ag concentrations, indicating an imbalance between TCR and coinhibitory signals regulating T cell release of IL-2. Exogenous IL-2 overrode coinhibitory B7-H1-mediated signals by LSECs and induced full CTL differentiation. Our results imply that LSEC-mediated T cell tolerance can be broken in situations where T cells bearing high-avidity TCR encounter LSECs cross-presenting high numbers of cognate MHC class I peptide molecules, such as during viral infection of the liver. Furthermore, we attribute a novel costimulatory function to IL-2 acting in a T cell autonomous fashion to promote local induction of immunity in the liver even in the absence of CD80/86 costimulation.
肝窦内皮细胞 (LSEC) 将可溶性 Ag 呈递到 MHC Ⅰ类分子上，进而诱导 naïve CD8 T 细胞，导致 T 细胞耐受，这一过程需要 LSEC 上的共抑制分子 B7-H1 与 CD8 T 细胞上的程序性死亡受体-1 相互作用。在本研究中，我们探讨了 LSEC 是否可以通过呈递高浓度和低浓度 Ag 诱导耐受。Ag 浓度与小鼠 LSEC 的交叉呈递能力直接相关，进而与 TCR 刺激强度相关。尽管低浓度 Ag 的 LSEC 交叉呈递导致耐受，但高浓度 Ag 诱导分化为效应 T 细胞（CTL）。在这些条件下，CTL 分化不是由于共刺激分子 CD80/86 在交叉呈递的 LSEC 上的表达增加引起，而是由 naïve CD8 T 细胞早期释放 IL-2 决定。来自 LSEC 的 B7-H1 信号和 TCR 亲和力共同控制早期 T 细胞 IL-2 的释放和 CTL 分化。LSEC 上的 B7-H1 表达与低浓度 Ag 的交叉呈递直接相关，但与高浓度 Ag 无关，表明调节 T 细胞释放 IL-2 的 TCR 和共抑制信号之间存在不平衡。外源性 IL-2 可克服 LSEC 介导的 B7-H1 共抑制信号，并诱导完全的 CTL 分化。我们的结果表明，在 T 细胞具有高亲和力 TCR 并遇到 LSEC 呈递大量同种 MHC Ⅰ类肽分子的情况下，如在肝脏病毒感染期间，LSEC 介导的 T 细胞耐受可能被打破。此外，我们将 IL-2 赋予了一种新的共刺激功能，即通过自主作用于 T 细胞促进肝脏局部免疫的诱导，即使在缺乏 CD80/86 共刺激的情况下也是如此。
