CXCL14 and Igsf8 are involved in double-stranded DNA and Alum adjuvant-mediated immune reaction.

The chemokine CXCL14 is known to bind CpG oligonucleotides and promote their uptake by dendritic cells and macrophages, thereby activating TLR9 in endosomes/lysosomes. However, it remains to be clarified whether CXCL14 also interacts with double-stranded DNA (dsDNA) and promotes its intracellular transportation. In this study, we demonstrate that CXCL14 forms a complex with dsDNA, and that this complex is internalized via immunoglobulin superfamily (Igsf) proteins. Furthermore, we found that stimulation with aluminum salt particles (Alum) adjuvant, which is involved in dsDNA-mediated innate immune responses, elicits IFN-β production in the presence of the CXCL14/dsDNA/Igsf8 complex. This result suggests that Igsf8-mediated intracellular delivery of the CXCL14/dsDNA complex is required for the Alum-induced Type I interferon responses. Finally, immunization with a SARS-CoV-2 spike protein together with the Alum adjuvant increased IgG1 antibody production in wild-type mice, but not in Igsf8-knockout mice. These results suggest that CXCL14 and Igsf8 are involved in the immune responses mediated by dsDNA and the Alum adjuvant.