A potent adjuvant effect of a CD1d-binding NKT cell ligand in human immune system mice

ABSTRACT

Objectives: A CD1d-binding invariant natural killer T (iNKT)-cell stimulatory glycolipid, namely 7DW8-5, is shown to enhance the efficacy of radiation-attenuated sporozoites (RAS)-based malaria vaccine in mice. In the current study, we aim to determine whether 7DW8-5 can display a potent adjuvant effect in human immune system (HIS) mice.

Methods: HIS-A2/hCD1d mice, which possess both functional human iNKT cells and CD8+ T cells, were generated by the transduction of NSG mice with adeno-associated virus serotype 9 expressing genes that encode human CD1d molecules and HLA-A*0201, followed by the engraftment of human hematopoietic stem cells. The magnitudes of human iNKT-cell response against 7DW8-5 and HLA-A*0201-restricted human CD8+ T-cell response against a human malaria antigen in HIS-A2/hCD1d mice were determined by using human CD1d tetramer and human HLA-A*0201 tetramer, respectively.

Results: We found that 7DW8-5 stimulates human iNKT cells in HIS-A2/hCD1d mice, as well as those derived from HIS-A2/hCD1d mice in vitro. We also found that 7DW8-5 significantly increases the level of a human malarial antigen-specific HLA-A*0201-restricted human CD8+ T-cell response in HIS-A2/hCD1d mice.

Conclusions: Our study indicates that 7DW8-5 can display a potent adjuvant effect on RAS vaccine-induced anti-malarial immunity by augmenting malaria-specific human CD8+ T-cell response.

KEYWORDS:

• Malaria
• sporozoites
• humanized mice
• adjuvant
• glycolipid
• CD1d
• NKT cell

Acknowledgment

We thank Dr. Vincent Sahi for assistance with flow cytometric analyses. We also thank the NIH tetramer Core Facility at Emory University for providing us with PBS-57-loaded human CD1d tetramer and YLNKIQNSL-loaded HLA-A*0201 tetramer.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by grants from the National Institutes of Health (R01-AI070258) and the Mark S. Bertuch AIDS Research Fund (both to M Tsuji) and from KAKENHI (26293091, 26305009, and 25253027) to M Yuda.