Elucidation of the mechanism by which a chemokine/DNA complex activates innate immunity

Chemokines are secreted proteins that promote leukocyte migration during an immune response, thereby contributing to inflammatory reactions. In 2017, Tanegashima et al. of Tokyo Metropolitan Institute of Medical Science discovered that in addition to its general function as a chemokine, CXCL14 binds to CpG DNA with high affinity. The CpG DNA/CXCL14 complex was transported efficiently into endosomes and lysosomes within dendritic cells, resulting in marked enhancement of innate immune responses (Fig. 1). The CpG DNA/CXCL14 complex dissociates under weakly acidic conditions; therefore, CXCL14 relays CpG DNA to TLR9 in endosomes and lysosomes that have a low pH. This relay mechanism revealed the importance of complex formation by CpG DNA and CXCL14. However, two things remained unclear: is this function common to other chemokines, and what is the mechanism underlying enhanced uptake of CpG DNA?

A new study from the same research group demonstrated that CXCL4, which is a different CXC type chemokine, has the same function as CXCL14 and enhances activation of dendritic cells in combination with CpG DNA. In addition, they showed that CXCL14 possesses distinct binding domains for CpG DNA and cell surface receptors, and that the CpG DNA/CXCL14 complex is incorporated into dendritic cells via the clathrin-dependent endocytosis pathway. Some deletion peptides of CXCL14, as well as chimeric CXCL12/CXCL14 peptides, bound to CpG DNA with high affinity, but did not enhance internalization of CpG DNA. These results suggest that formation of complexes comprising CpG DNA and chemokines is necessary, but not sufficient, for enhancement of CpG DNA internalization. 

The structure of the CpG DNA/CXCL14 complex was also analyzed using simulation software. The results showed that multiple amino acids at the N-terminal and C-terminal ends of CXCL14 act co-operatively to stabilize binding to CpG DNA (Fig. 2). The affinity of CXCL14 for CpG DNA is much higher than that of other chemokines and bactericidal peptides. This study provides molecular evidence supporting the very high affinity binding of CXCL14 to CpG DNA. 

Both CpG DNA and CXCL14 are associated with cancer immunosurveillance. Importantly, CpG DNA is expected to function in dendritic cells as a vaccine adjuvant. This new study strongly predicts the existence of a CXCL14 receptor that mediates internalization of CpG DNA. Identification of the receptor molecule will be critical for delivery of CpG DNA for therapeutic purposes.

About the Tokyo Metropolitan Institute of Medical Science

The Tokyo Metropolitan Institute of Medical Science (TMIMS) is dedicated to advancing basic and medical research in order to improve human health and quality of life. Founded in 2011 through the consolidation of three medical institutes, TMIMS is funded by the Tokyo metropolitan government and supports basic research in molecular and cellular biology in areas including genome replication, protein degradation, and infectious and neurodegenerative diseases. TMIMS also supports the development of new technologies in areas such as genome editing, control of neural prostheses, and vaccine development, and clinical research in fields such as optimization of nursing care and development of new treatments for psychiatric, neurodegenerative and other diseases. By integrating top-down applied research with bottom-up basic research, a goal of TMIMS is to more efficiently translate basic research results into treatments beneficial for humankind. For more information about TMIMS, see www.igakuken.or.jp/english.