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Elucidating the Motif for CpG Oligonucleotide Binding to the Dendritic Cell Receptor DEC-205 Leads to Improved Adjuvants for Liver-Resident Memory
The Journal of Immunology ( IF 3.6 ) Pub Date : 2021-10-01 , DOI: 10.4049/jimmunol.2001153
Jessica Li 1, 2 , Fatma Panetta 1 , Meredith O’Keeffe 1 , Ingrid M. Leal Rojas 3 , Kristen J. Radford 3 , Jian-Guo Zhang 4, 5 , Daniel Fernandez-Ruiz 2, 6 , Gayle M. Davey 2 , Benjamin S. Gully 1, 7 , Kirsteen M. Tullett 1 , Jamie Rossjohn 1, 7, 8 , Richard Berry 1, 7 , Chin-Nien Lee 9 , Mireille H. Lahoud 1 , William R. Heath 2, 6 , Irina Caminschi 1, 2
Affiliation  

DEC-205 is a cell-surface receptor that transports bound ligands into the endocytic pathway for degradation or release within lysosomal endosomes. This receptor has been reported to bind a number of ligands, including keratin, and some classes of CpG oligodeoxynucleotides (ODN). In this study, we explore in detail the requirements for binding ODNs, revealing that DEC-205 efficiently binds single-stranded, phosphorothioated ODN of ≥14 bases, with preference for the DNA base thymidine, but with no requirement for a CpG motif. DEC-205 fails to bind double-stranded phosphodiester ODN, and thus does not bind the natural type of DNA found in mammals. The ODN binding preferences of DEC-205 result in strong binding of B class ODN, moderate binding to C class ODN, minimal binding to P class ODN, and no binding to A class ODN. Consistent with DEC-205 binding capacity, induction of serum IL-12p70 or activation of B cells by each class of ODN correlated with DEC-205 dependence in mice. Thus, the greater the DEC-205 binding capacity, the greater the dependence on DEC-205 for optimal responses. Finally, by covalently linking a B class ODN that efficiently binds DEC-205, to a P class ODN that shows poor binding, we improved DEC-205 binding and increased adjuvancy of the hybrid ODN. The hybrid ODN efficiently enhanced induction of effector CD8 T cells in a DEC-205–dependent manner. Furthermore, the hybrid ODN induced robust memory responses, and was particularly effective at promoting the development of liver tissue–resident memory T cells.



中文翻译:

阐明 CpG 寡核苷酸与树突细胞受体 DEC-205 结合的基序可改善肝脏驻留记忆的佐剂

DEC-205 是一种细胞表面受体,可将结合的配体转运到内吞途径中,以便在溶酶体内体内降解或释放。据报道,该受体可结合多种配体,包括角蛋白和某些类别的 CpG 寡脱氧核苷酸 (ODN)。在这项研究中,我们详细探讨了结合 ODN 的要求,揭示了 DEC-205 有效结合 ≥14 个碱基的单链硫代磷酸化 ODN,优先结合 DNA 碱基胸苷,但不需要 CpG 基序。DEC-205 不能结合双链磷酸二酯 ODN,因此不能结合哺乳动物中发现的天然 DNA 类型。DEC-205 的 ODN 绑定偏好导致 B 类 ODN 的强结合、C 类 ODN 的中等结合、P 类 ODN 的最小结合,以及与 A 类 ODN 的无结合。与 DEC-205 结合能力一致,每类 ODN 诱导血清 IL-12p70 或激活 B 细胞与小鼠中的 DEC-205 依赖性相关。因此,DEC-205 结合能力越大,最佳反应对 DEC-205 的依赖性越大。最后,通过将有效结合 DEC-205 的 B 类 ODN 与显示较差结合的 P 类 ODN 共价连接,我们改善了 DEC-205 的结合并增加了混合 ODN 的辅助作用。杂交ODN以DEC-205依赖性方式有效增强效应CD8 T细胞的诱导。此外,混合 ODN 诱导了强大的记忆反应,并且在促进肝组织驻留记忆 T 细胞的发育方面特别有效。DEC-205 结合能力越大,最佳反应对 DEC-205 的依赖性越大。最后,通过将有效结合 DEC-205 的 B 类 ODN 与显示较差结合的 P 类 ODN 共价连接,我们改善了 DEC-205 的结合并增加了混合 ODN 的辅助作用。杂交ODN以DEC-205依赖性方式有效增强效应CD8 T细胞的诱导。此外,混合 ODN 诱导了强大的记忆反应,并且在促进肝组织驻留记忆 T 细胞的发育方面特别有效。DEC-205 结合能力越大,最佳反应对 DEC-205 的依赖性越大。最后,通过将有效结合 DEC-205 的 B 类 ODN 与显示较差结合的 P 类 ODN 共价连接,我们改善了 DEC-205 的结合并增加了混合 ODN 的辅助作用。杂交ODN以DEC-205依赖性方式有效增强效应CD8 T细胞的诱导。此外,混合 ODN 诱导了强大的记忆反应,并且在促进肝组织驻留记忆 T 细胞的发育方面特别有效。杂交ODN以DEC-205依赖性方式有效增强效应CD8 T细胞的诱导。此外,混合 ODN 诱导了强大的记忆反应,并且在促进肝组织驻留记忆 T 细胞的发育方面特别有效。杂交ODN以DEC-205依赖性方式有效增强效应CD8 T细胞的诱导。此外,混合 ODN 诱导了强大的记忆反应,并且在促进肝组织驻留记忆 T 细胞的发育方面特别有效。

更新日期:2021-09-21
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