Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement
Complement component C3d-antigen complexes can either augment or inhibit B lymphocyte activation and humoral immunity in mice depending on the degree of CD21/CD19 complex engagement
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DOI：
10.4049/jimmunol.175.12.8011
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发表时间：
2005-12-15
影响因子：
4.4
通讯作者：
Tedder, TF
中科院分区：
文献类型：
--
作者：
Lee, Y;Haas, KM;Tedder, TF
C3d可以通过结合CD21发挥分子佐剂的作用，从而增强B细胞的激活和体液免疫应答。然而，最近的研究表明，C3d和CD19/CD21信号复合体在调节体液免疫中既有积极的作用，也有消极的作用。为了探讨CD19/CD21复合体在生理配体激活时是否可以负向调节B细胞的功能，我们使用白喉毒素(DT)-C3d融合蛋白和C3dg-链霉亲和素(SA)复合体来评估CD21在BCR诱导的激活和体内免疫应答中的作用。用DT-C3d(3)免疫小鼠，显著降低DT特异性抗体反应，而不依赖于CD21的表达或信号。相比之下，SA-C3dg四聚体在低剂量使用时显著增强抗SA反应，而10倍高剂量则不能增强免疫反应，CD21/35缺陷小鼠除外。同样，SA-C3dg(1mU g/ml)可显著增强BCR诱导的细胞内钙离子浓度([Ca~(2+)](I))反应，但在10~50倍的浓度下，SA-C3dg对[Ca~(2+)](I)反应无影响或抑制。SA-C3dg增强BCR诱导的[Ca~(2+)](I)反应需要CD21和CD19的表达，并导致CD19和Lyn磷酸化显著增强，同时Lyn/CD19结合增强。Bcr诱导的CD22磷酸化和含有Src同源2结构域的蛋白酪氨酸磷酸酶-1/CD22的关联也被降低，这表明负调控信号被取消。相反，使用较高浓度的SA-C3dg结扎CD19/CD21可显著抑制BCR诱导的[Ca~(2+)](I)反应，并抑制CD19、Lyn、CD22和Syk的磷酸化。因此，C3d可能通过CD21依赖和非依赖的机制增强或抑制Ag特异性体液免疫应答，这取决于Ag-C3d复合体的浓度和性质。
C3d can function as a molecular adjuvant by binding CD21 and thereby enhancing B cell activation and humoral immune responses. However, recent studies suggest both positive and negative roles for C3d and the CD19/CD21 signaling complex in regulating humoral immunity. To address whether signaling through the CD19/CD21 complex can negatively regulate B cell function when engaged by physiological ligands, diphtheria toxin (DT)-C3d fusion protein and C3dg-streptavidin (SA) complexes,were used to assess the role of CD21 during BCR-induced activation and in vivo immune responses. Immunization of mice with DT-C3d(3), significantly reduced DT-specific Ab responses independently of CD21 expression or signaling. By contrast, SA-C3dg tetramers dramatically enhanced anti-SA responses when used at low doses, whereas 10-fold higher doses did not augment immune responses, except in CD21/35-deficient mice. Likewise, SA-C3dg (1 mu g/ml) dramatically enhanced BCR-induced intracellular calcium concentration ([Ca2+] (i)) responses in vitro, but had no effect or inhibited [Ca2+](i) responses when used at 10- to 50-fold higher concentrations. SA-C3dg enhancement of BCR-induced [Ca2+](i) responses required CD21 and CD19 expression and resulted in significantly enhanced CD19 and Lyn phosphorylation, with enhanced Lyn/CD19 associations. BCR-induced CD22 phosphorylation and Src homology 2 domain-containing protein tyrosine phosphatase-1/CD22 associations were also reduced, suggesting abrogation of negative regulatory signaling. By contrast, CD19/CD21 ligation using higher concentrations of SA-C3dg significantly inhibited BCR-induced [Ca2+](i) responses and inhibited CD19, Lyn, CD22, and Syk phosphorylation. Therefore, C3d may enhance or inhibit Ag-specific humoral immune responses through both CD21-dependent and -independent mechanisms depending on the concentration and nature of the Ag-C3d complexes.