Bower Joseph F, Ross Ted M
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15261, USA.
Adv Exp Med Biol. 2006;586:249-64. doi: 10.1007/0-387-34134-X_17.
The degradation product of the third (C3) complement component, C3d, links innate and adaptive immunity, and the covalent attachment of C3d to an antigen enhances antigen-specific immune responses. C3d has been hypothesized to enhance immunity by direct interaction with complement receptor 2 (CR2/CD21) on immune cells. However, the domains on C3d important for CR2 binding have been controversial, with various studies reaching contradictory conclusions. In addition, the concept of B-cell activation via CR2 by C3d has been questioned, since mice lacking CR2 still elicit C3d-enhanced immunity following vaccination. Therefore, the goal of this study was to determine if a peptide representing one of the proposed CR2 binding domains of C3d could substitute for the entire protein and enhance antigen-specific immunity. Mice (BALB/c) were vaccinated with the HIV-1 gp120 envelope glycoprotein (Env(gp120)) alone or fused to multiple copies of the murine C3d or a twenty-eight amino-acid peptide (P28) containing a minimum CR2 binding domain. Each immunogen was expressed from DNA plasmid in vivo or injected as purified recombinant protein. The fusion of the P28 peptide to Env(gp120) enhanced both humoral and cell-mediated immune responses with similar efficiency as Env(gp120) conjugated to C3d. The fusion of C3d or P28 to Env(gp120) elicited higher-titer anti-Env specific antibody, enhanced avidity maturation of the elicited antibody, and elicited higher numbers of IFN-gamma and IL-4 secreting cells compared to Env(gp120) immunizations. This CR2-binding domain specific 28 amino acid peptide can substitute for the entire C3d molecule and enhance immunity. These results indicate that the adjuvant properties of C3d are associated with CR2 interaction.
补体第三成分（C3）的降解产物C3d连接天然免疫和适应性免疫，C3d与抗原的共价连接可增强抗原特异性免疫反应。据推测，C3d通过与免疫细胞上的补体受体2（CR2/CD21）直接相互作用来增强免疫力。然而，C3d上对CR2结合重要的结构域一直存在争议，各种研究得出了相互矛盾的结论。此外，C3d通过CR2激活B细胞的概念也受到质疑，因为缺乏CR2的小鼠在接种疫苗后仍能引发C3d增强的免疫反应。因此，本研究的目的是确定一种代表C3d拟议的CR2结合结构域之一的肽是否可以替代整个蛋白质并增强抗原特异性免疫。用HIV-1 gp120包膜糖蛋白（Env(gp120)）单独或与多个小鼠C3d拷贝或含有最小CR2结合结构域的28个氨基酸肽（P28）融合对小鼠（BALB/c）进行免疫接种。每种免疫原通过体内DNA质粒表达或作为纯化的重组蛋白注射。P28肽与Env(gp120)的融合增强了体液免疫和细胞介导的免疫反应，其效率与与C3d偶联的Env(gp120)相似。与Env(gp120)免疫相比，C3d或P28与Env(gp120)的融合引发了更高滴度的抗Env特异性抗体，增强了所引发抗体的亲和力成熟，并引发了更多分泌IFN-γ和IL-4的细胞。这种CR2结合结构域特异性的28氨基酸肽可以替代整个C3d分子并增强免疫力。这些结果表明，C3d的佐剂特性与CR2相互作用有关。
