Elucidating the motif for cpg oligonucleotide binding to the dendritic cell receptor dec-205 leads to improved adjuvants for liver-resident memory

Jessica Li, Fatma Panetta, Meredith O'Keeffe, Ingrid M.Leal Rojas, Kristen J. Radford, Jian-Guo Zhang, Daniel Fernandez-Ruiz, Gayle M. Davey, Benjamin S. Gully, Kirsteen M. Tullett, Jamie Rossjohn, Richard Berry, Chin Nien Lee, Mireille H. Lahoud, William R. Heath, Irina Caminschi

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Abstract

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.

Original languageEnglish
Pages (from-to)1836-1847
Number of pages12
JournalJournal of Immunology
Volume207
Issue number7
DOIs
Publication statusPublished - 1 Oct 2021

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