Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY 14214, USA.
J Leukoc Biol. 2011 Nov;90(5):911-21. doi: 10.1189/jlb.0511236. Epub 2011 Jul 26.
A host of human pathogens invades the body at mucosal surfaces. Yet, strong, protective mucosal immune responses directed against those pathogens routinely cannot be induced without the use of adjuvants. Although the strongest mucosal adjuvants are members of the family of HLTs, the inherent toxicities of HLT holotoxins preclude their clinical use. Herein, it is shown that LT-IIa-B(5) enhances mucosal immune responses by modulating activities of DCs. i.n. immunization of mice with OVA in the presence of LT-IIa-B(5) recruited DCs to the NALT and significantly increased uptake of OVA by those DCs. Furthermore, LT-IIa-B(5) increased expression of CCR7 by DCs, which mediated enhanced migration of the cells from the NALT to the draining CLNs. LT-IIa-B(5) also enhanced maturation of DCs, as revealed by increased surface expression of CD40, CD80, and CD86. Ag-specific CD4(+) T cell proliferation was augmented in the CLNs of mice that had received i.n. LT-IIa-B(5). Finally, when used as an i.n. adjuvant, LT-IIa-B(5) dramatically increased the levels of OVA-specific salivary IgA and OVA-specific serum IgG. Strikingly, each of the activities induced by LT-IIa-B(5) was strictly TLR2-dependent. The data strongly suggest that the immunomodulatory properties of LT-IIa-B(5) depend on the productive modulation of mucosal DCs. Notably, this is the first report for any HLT to demonstrate in vivo the elicitation of strong, TLR2-dependent modulatory effects on DCs with respect to adjuvanticity.
大量的人类病原体在黏膜表面侵袭人体。然而，如果不使用佐剂，针对这些病原体的强大的保护性黏膜免疫反应通常是无法诱导的。虽然最强的黏膜佐剂是 HLTS 家族的成员，但 HLTS 全毒素的固有毒性排除了它们的临床应用。本文表明，LT-IIa-B(5)通过调节 DC 的活性增强黏膜免疫反应。在 LT-IIa-B(5)存在的情况下，通过鼻腔内免疫给小鼠接种 OVA，可将 DC 募集到 NALT，并显著增加这些 DC 对 OVA 的摄取。此外，LT-IIa-B(5)增加了 DC 表达 CCR7，介导细胞从 NALT 向引流的 CLN 的增强迁移。LT-IIa-B(5)还增强了 DC 的成熟，表现为 CD40、CD80 和 CD86 的表面表达增加。在接受鼻腔内 LT-IIa-B(5)的小鼠的 CLN 中，Ag 特异性 CD4(+)T 细胞增殖得到增强。最后，当用作鼻腔内佐剂时，LT-IIa-B(5)显著增加了 OVA 特异性唾液 IgA 和 OVA 特异性血清 IgG 的水平。引人注目的是，LT-IIa-B(5)诱导的每种活性都严格依赖 TLR2。数据强烈表明，LT-IIa-B(5)的免疫调节特性依赖于对黏膜 DC 的有效调节。值得注意的是，这是第一个报告任何 HLTS 在体内对 TLR2 具有强烈的、依赖 TLR2 的调节作用，从而具有佐剂作用。
