Gagliardi M C, Sallusto F, Marinaro M, Langenkamp A, Lanzavecchia A, De Magistris M T
Laboratory of Bacteriology and Medical Mycology, Istituto Superiore di Sanità, Rome, Italy.
Eur J Immunol. 2000 Aug;30(8):2394-403. doi: 10.1002/1521-4141(2000)30:8<2394::AID-IMMU2394>3.0.CO;2-Y.
Cholera toxin (CT) is a potent mucosal adjuvant that amplifies B and T cell responses to mucosally co-administered antigens, stimulating predominant Th2-type responses. However, little is known about the mechanism of adjuvanticity of CT and on the influence this toxin may have on Th2 cell development during the priming of an immune response. We analyzed the effect of CT on dendritic cells (DC), which are responsible for the priming of immune responses at the systemic as well as at the mucosal level. We found that CT induces phenotypic and functional maturation of blood monocyte-derived DC. Indeed, CT-treated DC up-regulate expression of HLA-DR molecules, B7. 1 and B7.2 co-stimulatory molecules, and are able to prime naive CD4(+)CD45RA(+) T cells in vitro, driving their polarization towards the Th2 phenotype. Furthermore, CT-matured DC express functional chemokine receptors CCR7 and CXCR4 which may render them responsive to migratory stimuli towards secondary lymphoid organs. Interestingly, the maturation program induced by CT is unique since CT does not induce but rather inhibits cytokine (IL-12p70 and TNF-alpha) and chemokine (RANTES, MIP-1alpha and MIP-1beta) secretion by lipopolysaccharide- or CD40 ligand-activated DC. Our results help to elucidate the mechanism of action of CT as an adjuvant and highlight a new stimulus of bacterial origin that promotes maturation of DC.
霍乱毒素（CT）是一种强效黏膜佐剂，可增强B细胞和T细胞对黏膜共同给药抗原的反应，刺激主要的Th2型反应。然而，关于CT的佐剂作用机制以及该毒素在免疫反应启动过程中对Th2细胞发育可能产生的影响，人们知之甚少。我们分析了CT对树突状细胞（DC）的作用，DC在全身和黏膜水平负责启动免疫反应。我们发现CT可诱导血液单核细胞来源的DC发生表型和功能成熟。实际上，经CT处理的DC上调了HLA-DR分子、B7.1和B7.2共刺激分子的表达，并且能够在体外启动未成熟的CD4(+)CD45RA(+) T细胞，促使它们向Th2表型极化。此外，经CT成熟的DC表达功能性趋化因子受体CCR7和CXCR4，这可能使它们对向次级淋巴器官迁移的刺激产生反应。有趣的是，CT诱导的成熟程序是独特的，因为CT不会诱导而是抑制脂多糖或CD40配体激活的DC分泌细胞因子（IL-12p70和TNF-α）和趋化因子（RANTES、MIP-1α和MIP-1β）。我们的结果有助于阐明CT作为佐剂的作用机制，并突出了一种促进DC成熟的新型细菌源刺激物。
