Thompson Bruce S, Chilton Paula M, Ward Jon R, Evans Jay T, Mitchell Thomas C
Institute for Cellular Therapeutics, Department of Microbiology and Immunology, University of Louisville, Donald Baxter Research Building, 570 S. Preston Street, Room 404C, Louisville, KY 40202, USA.
J Leukoc Biol. 2005 Dec;78(6):1273-80. doi: 10.1189/jlb.0305172. Epub 2005 Oct 4.
Lipopolysaccharide (LPS) has long been known to enhance innate and adaptive immune responses; however, its extreme toxicity precludes its use in clinical settings. The combined toxicity and adjuvanticity of LPS have contributed to the view that immunological adjuvants need to be highly inflammatory to be maximally effective. Here, we compared the effects of LPS with its less-toxic derivatives, monophosphoryl lipid A (MPL) and a chemical mimetic, RC529, on CD4+ T cell clonal expansion, long-term survival, and T helper cell type 1 (Th1) differentiation. We found that LPS, MPL, and RC529 had similar effects on CD4+ T cell clonal expansion, cell division, and ex vivo survival. Analysis of the ability of activated CD4+ T cells to produce interferon-gamma following a 21-day immunization and challenge protocol with LPS and MPL resulted in similar Th1 differentiation. In contrast, we found that LPS was more effective in promoting long-term CD4+ T cell responses, as we recovered nearly sixfold more cells following immunization/challenge as compared with treatment with MPL. Our results indicate that low-inflammation adjuvants, such as MPL and RC529, are capable of enhancing short-term CD4+ T cell clonal expansion and Th1 differentiation, but inflammatory signaling aids in the long-term retention of antigen-specific T cells.
长期以来，人们一直知道脂多糖（LPS）可增强先天性和适应性免疫反应；然而，其极高的毒性使其无法用于临床。LPS的毒性和佐剂性共同导致了这样一种观点，即免疫佐剂需要具有高度炎症性才能发挥最大效果。在此，我们比较了LPS与其毒性较低的衍生物单磷酰脂质A（MPL）和一种化学模拟物RC529对CD4+T细胞克隆扩增、长期存活以及1型辅助性T细胞（Th1）分化的影响。我们发现，LPS、MPL和RC529对CD4+T细胞克隆扩增、细胞分裂和体外存活具有相似的影响。在用LPS和MPL进行21天免疫和激发方案后，分析活化的CD4+T细胞产生干扰素-γ的能力，结果显示Th1分化相似。相比之下，我们发现LPS在促进长期CD4+T细胞反应方面更有效，因为与MPL处理相比，免疫/激发后我们回收的细胞数量多出近六倍。我们的结果表明，低炎症性佐剂，如MPL和RC529，能够增强短期CD4+T细胞克隆扩增和Th1分化，但炎症信号有助于长期保留抗原特异性T细胞。
