Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 2010 Jun 15;184(12):6766-72. doi: 10.4049/jimmunol.0904054. Epub 2010 May 12.
Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall Ags. Because sepsis induces significant apoptosis in lymphoid and myeloid cells, and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture demonstrated a loss of DTH for the 7 d following cecal ligation and puncture; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim-/- mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when TRAIL null mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell that suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.
严重脓毒症患者常表现出严重的免疫功能受损。脓毒症患者免疫抑制的一个标志是迟发型超敏反应（DTH）受损，表现为对回忆抗原的皮肤试验丧失。由于脓毒症诱导淋巴样和髓样细胞发生显著的细胞凋亡，而凋亡细胞本身具有免疫耐受特性，因此我们检验了这样一种假设，即在脓毒症期间产生的具有免疫耐受特性的凋亡细胞介导了 DTH 的抑制。接受盲肠结扎和穿刺的小鼠在盲肠结扎和穿刺后 7 天内表现出 DTH 丧失；然而，到第 10 天，免疫反应恢复正常。通过 Bcl-2 过表达或 Bim 缺陷来阻断脓毒症诱导的细胞凋亡可防止 DTH 的丧失。重要的是，将凋亡细胞注射到 Bim-/-小鼠中可防止有效的 DTH 反应，从而提示凋亡细胞与免疫抑制之间存在因果关系。令人惊讶的是，当检查 TRAIL 缺失小鼠时，我们发现这些动物有明显的细胞凋亡，但仍保留 DTH 反应。进一步的研究表明，脓毒症期间产生的凋亡细胞诱导了 CD8+调节性 T 细胞，通过 TRAIL 的产生来抑制 DTH。这些结果确立了脓毒症期间凋亡细胞与免疫抑制之间的联系，并表明 TRAIL 可能是增强脓毒症后适应性免疫反应的一个可行的治疗靶点。
