Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA.
J Immunol. 2010 Mar 1;184(5):2410-22. doi: 10.4049/jimmunol.0902994. Epub 2010 Jan 25.
Costimulatory signals via B7/CD28 family molecules (signal 2) are critical for effective adaptive CD8(+) T cell immune responses. In addition to costimulatory signals, B7/CD28 family coinhibitory receptor/ligands that modulate immune responses have been identified. In acute hepatitis C virus (HCV) infection, programmed death receptor 1, an inhibitory receptor in the CD28 family, is highly expressed on virus-specific CD8(+) T cells, yet vigorous immune responses often develop. We hypothesized that other costimulatory signals present during the acute phase of HCV infection would be important to counter this negative signaling. In this study, we found that CD86 was highly expressed on HCV-specific CD8(+) T cells early in acute HCV infection and was lost on transition to chronic HCV infection; the expression of CD86 was different from other activation markers, because expression was delayed after in vitro TCR stimulation and required sufficient IL-2 signaling; and HCV-specific CD8(+) T cells in the liver of patients with chronic HCV infection were highly activated (CD69, CD38, and HLA-DR expression), but only a minority expressed CD86 or showed evidence of recent IL-2 signaling (low basal phosphorylated STAT5), despite persistent viremia. Our study identified B7 ligand expression on HCV-specific CD8(+) T cells as a distinct marker of effective T cell stimulation with IL-2 signaling in acute HCV infection. Expression of costimulatory molecules, such as CD86, early in HCV infection may be essential in overcoming inhibitory signals from the high level of programmed death receptor 1 expression also seen at this phase of infection.
共刺激信号通过 B7/CD28 家族分子（信号 2）对于有效的适应性 CD8(+)T 细胞免疫反应至关重要。除了共刺激信号外，还鉴定了调节免疫反应的 B7/CD28 家族共抑制受体/配体。在急性丙型肝炎病毒（HCV）感染中，CD28 家族中的抑制性受体程序性死亡受体 1（PD-1）在病毒特异性 CD8(+)T 细胞上高度表达，但通常会产生强烈的免疫反应。我们假设在 HCV 感染的急性期存在其他共刺激信号对于抵消这种负信号很重要。在这项研究中，我们发现 CD86 在急性 HCV 感染早期在 HCV 特异性 CD8(+)T 细胞上高度表达，并在过渡到慢性 HCV 感染时丢失；CD86 的表达与其他激活标记物不同，因为其表达在体外 TCR 刺激后延迟，并且需要足够的 IL-2 信号；慢性 HCV 感染患者肝脏中的 HCV 特异性 CD8(+)T 细胞高度激活（CD69、CD38 和 HLA-DR 表达），但只有少数表达 CD86 或表现出最近 IL-2 信号的证据（基础磷酸化 STAT5 低），尽管持续存在病毒血症。我们的研究确定了 HCV 特异性 CD8(+)T 细胞上 B7 配体的表达作为急性 HCV 感染中 IL-2 信号有效刺激 T 细胞的独特标志物。在 HCV 感染的早期阶段表达共刺激分子（如 CD86）可能对于克服高水平程序性死亡受体 1 表达所带来的抑制信号至关重要，在感染的这一阶段也可以看到高水平的程序性死亡受体 1 表达。
