Hu John C, Greene Christopher J, King-Lyons Natalie D, Connell Terry D
Department of Microbiology & Immunology, The Witebsky Center for Microbial Pathogenesis and Immunology, The University at Buffalo, Buffalo, New York, United States of America.
PLoS One. 2015 Nov 13;10(11):e0142942. doi: 10.1371/journal.pone.0142942. eCollection 2015.
Poor immune responses elicited by vaccine antigens can be enhanced by the use of appropriate adjuvants. Type II heat-labile enterotoxins (HLT) produced by Escherichia coli are extremely potent adjuvants that augment both humoral and cellular immunity to co-administered antigens. Recent findings demonstrate that LT-IIb and LT-IIc, two type II HLT adjuvants, exhibit potent, yet distinguishable CD8(+) T cell adjuvant properties. While LT-IIc elicits a robust and rapid response at one week after administration, LT-IIb engenders a more gradual and slower expansion of antigen-specific CD8(+) T cells that correlates with improved immunity. The variations in immune effects elicited by the HLT adjuvants have been generally attributed to their highly divergent B subunits that mediate binding to various gangliosides on cell surfaces. Yet, HLT adjuvants with point mutations in the B subunit that significantly alter ganglioside binding retain similar adjuvant functions. Therefore, the contribution of the B subunits to adjuvanticity remains unclear. To investigate the influence of the B subunits on the enhancement of immune responses by LT-IIb and LT-IIc, chimeric HLT were engineered in which the B subunits of the two adjuvants were exchanged. Comparing the immune potentiating characteristics of both native and chimeric HLT adjuvants, it was found that not all the adjuvant characteristics of the HLT adjuvants were modulated by the respective B subunits. Specifically, the differences in the CD8(+) T cell kinetics and protective responses elicited by LT-IIb and LT-IIc did indeed followed their respective B subunits. However, induction of IL-1 from macrophages and the capacity to intoxicate cells in a mouse Y1 adrenal cell bioassay did not correlate with the B subunits. Therefore, it is likely that additional factors other than the B subunits contribute to the effects elicited by the HLT adjuvants.
使用合适的佐剂可以增强疫苗抗原引发的不良免疫反应。大肠杆菌产生的II型不耐热肠毒素（HLT）是极其有效的佐剂，可增强对共同给药抗原的体液免疫和细胞免疫。最近的研究结果表明，两种II型HLT佐剂LT-IIb和LT-IIc具有强大但可区分的CD8(+) T细胞佐剂特性。虽然LT-IIc在给药后一周引发强烈而快速的反应，但LT-IIb会使抗原特异性CD8(+) T细胞逐渐且缓慢地扩增，这与免疫力的提高相关。HLT佐剂引发的免疫效应差异通常归因于其高度不同的B亚基，这些亚基介导与细胞表面各种神经节苷脂的结合。然而，B亚基中具有显著改变神经节苷脂结合的点突变的HLT佐剂仍保留相似的佐剂功能。因此，B亚基对佐剂活性的贡献仍不清楚。为了研究B亚基对LT-IIb和LT-IIc增强免疫反应的影响，构建了嵌合HLT，其中两种佐剂的B亚基进行了交换。比较天然和嵌合HLT佐剂的免疫增强特性，发现并非所有HLT佐剂的佐剂特性都受各自B亚基的调节。具体而言，LT-IIb和LT-IIc引发的CD8(+) T细胞动力学和保护性反应的差异确实遵循各自的B亚基。然而，巨噬细胞诱导IL-1的能力以及在小鼠Y1肾上腺细胞生物测定中使细胞中毒的能力与B亚基无关。因此，除了B亚基之外，可能还有其他因素导致HLT佐剂产生这些效应。
