TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells

Xiao Sun; Koji Hosomi; Atsushi Shimoyama; Ken Yoshii; Huangwenxian Lan; Yunru Wang; Haruki Yamaura; Takahiro Nagatake; Ken J Ishii; Shizuo Akira; Hiroshi Kiyono; Koichi Fukase; Jun Kunisawa

doi:10.1016/j.intimp.2023.109852

TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells

Int Immunopharmacol. 2023 Apr:117:109852. doi: 10.1016/j.intimp.2023.109852. Epub 2023 Feb 18.

Authors

Xiao Sun¹, Koji Hosomi², Atsushi Shimoyama³, Ken Yoshii⁴, Huangwenxian Lan¹, Yunru Wang¹, Haruki Yamaura⁵, Takahiro Nagatake⁶, Ken J Ishii⁷, Shizuo Akira⁸, Hiroshi Kiyono⁹, Koichi Fukase³, Jun Kunisawa¹⁰

Affiliations

¹ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
² Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
³ Graduate School of Science, Osaka University, Osaka, Japan; Collaborative Research between NIBIOHN and Graduate School of Science, Forefront Research Center, Osaka University, Osaka, Japan.
⁴ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Medicine, Osaka University, Osaka, Japan.
⁵ Graduate School of Science, Osaka University, Osaka, Japan.
⁶ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Laboratory of Functional Anatomy, Department of Life Sciences, School of Agriculture, Meiji University, Kanagawa, Japan.
⁷ International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Immunology Frontier Research Center, Osaka University, Osaka, Japan; Center for Vaccine and Adjuvant Research (CVAR), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
⁸ Immunology Frontier Research Center, Osaka University, Osaka, Japan.
⁹ International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), San Diego, CA, United States; Chiba University (CU)-UCSD Center for Mucosal Immunology, Allergy and Vaccines (cMAV), UCSD, San Diego, CA, United States; Future Medicine Education and Research Organization, Chiba University, Chiba, Japan; Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan; Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁰ Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan; Graduate School of Science, Osaka University, Osaka, Japan; Collaborative Research between NIBIOHN and Graduate School of Science, Forefront Research Center, Osaka University, Osaka, Japan; Graduate School of Medicine, Osaka University, Osaka, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan; Research Organization for Nano and Life Innovation, Waseda University, Tokyo, Japan; Graduate School of Dentistry, Osaka University, Suita, Japan. Electronic address: kunisawa@nibiohn.go.jp.

PMID: 36806039
DOI: 10.1016/j.intimp.2023.109852

Abstract

Alcaligenes faecalis was previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we compared A. faecalis lipid A (ALA) with monophosphoryl lipid A, a licensed lipid A-based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA-TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways.

Keywords: Alcaligenes; Lipid A; MPLA; MyD88; TRIF, Th17.

MeSH terms

Adaptor Proteins, Vesicular Transport / metabolism
Adjuvants, Immunologic / pharmacology
Alcaligenes / metabolism
Antigen Presentation
Cell Differentiation
Dendritic Cells
Lipid A* / metabolism
Lipid A* / pharmacology
Myeloid Differentiation Factor 88* / metabolism
Signal Transduction
Toll-Like Receptor 4 / metabolism

Substances

Lipid A
Myeloid Differentiation Factor 88
Toll-Like Receptor 4
Adjuvants, Immunologic
Adaptor Proteins, Vesicular Transport