Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis

Inuki, Shinsuke; Hirata, Natsumi; Kashiwabara, Emi; Kishi, Junichiro; Aiba, Toshihiko; Teratani, Toshiaki; Nakamura, Wataru; Kojima, Yoshimi; Maruyama, Toru; Kanai, Takanori; Fujimoto, Yukari

doi:10.1038/s41598-020-72280-4

Cited by 10 publications

(4 citation statements)

References 51 publications

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“…Th2-polarizing iNKT cell agonists are attractive potential candidates for adjuvants and therapeutic drugs. In addition to C20:2 and OCH, other Th2-type αGC analogues with novel modifications have appeared in recent decades. − , Unfortunately, the majority of them were evaluated in vitro, or assessed through serum levels of IFN-γ and IL-4 after intraperitoneal or intravenous injection of the glycolipids, or used as a single agent in autoimmune disease models (such as PBS-25, Bz amide-containing αGC derivative), with only a few Th2 analogues investigated as vaccine adjuvants (such as KBC009, , αGC-MPEG). Notably, even though an in vivo cytokine assay on serum revealed a Th2 cytokine profile, KBC009 and αGC-MPEG induced robust neutralizing antibody responses.…”

Section: Discussionmentioning

confidence: 99%

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses

Cheng

Wang

et al. 2022

ACS Infect. Dis.

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Adjuvants are essential components of vaccines. Invariant natural killer T (iNKT) cells are a distinct subset of T cells that function to bridge the innate and adaptive immunities and are capable of mediating strong and rapid responses to a range of diseases, including cancer and infectious disease. An increasing amount of evidence suggests that iNKT cells can help fight viral infection. In particular, iNKT-secreting IL-4 is a key mediator of humoral immunity and has a positive correlation with the levels of neutralizing antibodies. As iNKT cell agonists, αGC glycolipid (αgalactosylceramide, or KRN7000) and its analogues as vaccine adjuvants have begun to provide vaccinologists with a new toolset. Herein we found that a new iNKT-cell agonist αGC-CPOEt elicited a strong cytokine response with increased IL-4 production. Remarkably, after three immunizations, SARS-CoV-2 RBD-Fc adjuvanted by αGC-CPOEt evoked robust neutralizing antibody responses that were about 5.5-fold more than those induced by αGC/RBD-Fc and 25-fold greater than those induced by unadjuvanted RBD-Fc. These findings imply that αGC-CPOEt could be investigated further as a new COVID-19 vaccine adjuvant to prevent current and future infectious disease outbreaks.

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Section: Discussionmentioning

confidence: 99%

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses

Cheng

Wang

et al. 2022

ACS Infect. Dis.

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“…Injection of OCH, a derivative of α-GalCer with Th2 selective activity, prevents DSS-induced colitis, which correlates with reduced Th1/Th2 cytokine ratios and increased IL-10 production ( 39 ). Treatment with an α-GalCer derivative containing polar functional groups (Bz amide) attenuates DSS-induced colitis, accompanied by expansion and activation of Th2- and Th17-biased iNKT cells rather than Th1-biased iNKT cells ( 40 ). Glycolipid Ags derived from the intestinal microbe B. fragilis (called GSL-Bf717 or BfaGCs) inhibit iNKT cell activation through competitive binding of their sphinganine branches with CD1d, resulting in protection against oxazolone (Oxa)-induced colitis, an experimental model mimicking UC ( 41 – 43 ).…”

Section: Effect Of Glycolipid-stimulated Inkt Cells On Ibdmentioning

confidence: 99%

Role of CD1d and iNKT cells in regulating intestinal inflammation

Lee,

Park,

Van Kaer

et al. 2024

Front. Immunol.

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Invariant natural killer T (iNKT) cells, a subset of unconventional T cells that recognize glycolipid antigens in a CD1d-dependent manner, are crucial in regulating diverse immune responses such as autoimmunity. By engaging with CD1d-expressing non-immune cells (such as intestinal epithelial cells and enterochromaffin cells) and immune cells (such as type 3 innate lymphoid cells, B cells, monocytes and macrophages), iNKT cells contribute to the maintenance of immune homeostasis in the intestine. In this review, we discuss the impact of iNKT cells and CD1d in the regulation of intestinal inflammation, examining both cellular and molecular factors with the potential to influence the functions of iNKT cells in inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

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“…32,33 These advancements have enabled NKT cell modulator applications for therapeutic agent development and vaccine adjuvants. 31,34,35 This leading situation in NKT cell activator development underscores the significance of exploring ligand design strategies for activating MAIT cells, which are more abundant than NKT cells in humans, 17,28 and creating a diverse range of easy-to-handle MAIT cell activators that can be used as potent tools in therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Development of Ribityllumazine Analogs as Mucosal-associated Invariant T Cell Activators

Takasaki,

Nagae,

Takahashi

et al. 2024

Preprint

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Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the last decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found chemically stable MAIT cell activators with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The activators showed high potency toward a co-cultivation assay using model cell lines of antigen-presenting cells and MAIT cells (EC50 = 20 nM). The X-ray crystallographic analysis revealed the binding mode of the activator to MR1 and T cell receptor, indicating that it forms a covalent bond with MR1 via Shiff base formation. Furthermore, we found that one activator stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed activator is one of the most potent among chemically stable MAIT cell activators, contributing to accelerating therapeutic applications of MAIT cells.

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Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis

Cited by 10 publications

References 51 publications

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses

A New iNKT-Cell Agonist-Adjuvanted SARS-CoV-2 Subunit Vaccine Elicits Robust Neutralizing Antibody Responses

Role of CD1d and iNKT cells in regulating intestinal inflammation

Development of Ribityllumazine Analogs as Mucosal-associated Invariant T Cell Activators

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