Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against malaria

Holz, Lauren E.; Chua, Yu Cheng; Anderson, Regan J.; Draper, Sarah; Compton, Benjamin J.; Chan, Susanna T. S.; Mathew, Juby; Menezes, Maria de; Cozijnsen, Anton; Mollard, Vanessa; McFadden, Geoffrey I.; Painter, Gavin F.; Heath, William R.

doi:10.4049/jimmunol.204.supp.168.1

Cited by 4 publications

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“…Resident memory T cells are crucial for local immunity and recall response, which is considered more potential subsets in vaccine designation (92). A recent study shows that induction of iNKT cell activation can promote the generation of liver-resident memory CD8 + T cells, which prevents malaria (93). In naïve mice raised in specific pathogen-free and germ-free conditions, a small CD8 + T-cell population displaying memorial phenotypes is named "virtual memory" CD8 + T cells (CD8 + T VM ).…”

Section: The Formation Of Memory Cd8 + T Cell Assisted By Inkt Cellsmentioning

confidence: 99%

CD8+ T-cell immunity orchestrated by iNKT cells

Qin

Bao²,

Zheng³

2023

Front. Immunol.

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CD8+ T cells belonging to the adaptive immune system play key roles in defending against viral infections and cancers. The current CD8+ T cell-based immunotherapy has emerged as a superior therapeutic avenue for the eradication of tumor cells and long-term prevention of their recurrence in hematologic malignancies. It is believed that an effective adaptive immune response critically relies on the help of the innate compartment. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that have been considered some of the first cells to respond to infections and can secrete a large amount of diverse cytokines and chemokines to widely modulate the innate and adaptive immune responders. Like CD8+ T cells, iNKT cells also play an important role in defense against intracellular pathogenic infections and cancers. In this review, we will discuss the CD8+ T-cell immunity contributed by iNKT cells, including iNKT cell-mediated cross-priming and memory formation, and discuss recent advances in our understanding of the mechanisms underlying memory CD8+ T-cell differentiation, as well as aging-induced impairment of T-cell immunity.

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Section: The Formation Of Memory Cd8 + T Cell Assisted By Inkt Cellsmentioning

confidence: 99%

CD8+ T-cell immunity orchestrated by iNKT cells

Qin

Bao²,

Zheng³

2023

Front. Immunol.

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“…Oxime ligation between carbonyl-containing compounds (i.e., aldehydes or ketones) and peptides functionalized with an aminooxy group is a proven way to efficiently generate glycolipid-peptide conjugate vaccines. 20,21,49 Conditions promoting oxime bond formation include the use of aniline catalysts under mildly acidic conditions (∼pH 3−5). 50 To investigate this ligation approach, the corresponding G0 vaccine construct was synthesized whereby α-GalCer amine 5 was reacted with the activated ester of 8-oxo-nonanoic acid (23) to give α-GalCer ketone 24 (Scheme 5).…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

et al. 2023

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Synthetic vaccines that induce T cell responses to peptide epitopes are a promising immunotherapy for both communicable and noncommunicable diseases. Stimulating strong and sustained T cell responses requires antigen delivery to appropriately activated antigen presenting cells (APCs). One way this can be accomplished is by chemically conjugating immunogenic peptide epitopes with α-galactosylceramide (α-GalCer), a glycolipid that acts as an immune adjuvant by inducing stimulatory interactions between APCs and type I natural killer T (NKT) cells. Here we investigate whether increasing the ratio of antigen:adjuvant improves antigen-specific T cell responses. A series of conjugate vaccines was prepared in which one, two, four, or eight copies of an immunogenic peptide were covalently attached to a modified form of α-GalCer via the poly(ethoxyethylglycinamide) dendron scaffold. Initial attempts to synthesize these multivalent conjugate vaccines involved attaching the bicyclo[6.1.0]non-4-yne (BCN) group to the adjuvant-dendron structure followed by strain-promoted azide–alkyne cycloaddition of the peptide. Although this approach was successful for preparing vaccines with either one or two peptide copies, the synthesis of vaccines requiring attachment of four or eight BCN groups suffered from low yields due to cyclooctyne degradation. Instead, conjugate vaccines containing up to eight peptide copies were readily achieved through oxime ligation with adjuvant-dendron constructs decorated with the 8-oxo-nonanoyl group. When evaluating T cell responses to vaccination in mice, we confirmed a significant advantage to conjugation over admixes of peptide and α-GalCer, regardless of the peptide to adjuvant ratio, but there was no advantage to increasing the number of peptides attached. However, it was notable that the higher ratio conjugate vaccines required lower levels of NKT cell activation to be effective, which could be a safety advantage for future vaccine candidates.

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“…RAS vaccination is considered the gold-standard for the generation of liver Trm and protection from malaria. This finding led to development of liver Trm cell generating vaccines that provide sterile protection from malaria [379][380][381][382] . Most notable are, "prime and trap" vaccination strategies that use either DNA vaccination or peptide-linked anti-CLEC9a…”

Section: Consistent With This Forced Klf2 Expression Which Abrogated ...mentioning

confidence: 99%

“…Trm cells in the brain produce a barrier that protects the brain from LCMV infection [406] . NKT cells can be exploited to generate powerful liver Trm responses that can protect from malaria [379,380] . Interestingly, NKT have been considered Trm cells in many contexts, as they are typically non-circulating [352] .…”

Section: Consistent With This Forced Klf2 Expression Which Abrogated ...mentioning

confidence: 99%

Generation of liver tissue-resident memory T cells with novel NKT cell agonists and mRNA vaccines

Ganley

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<p dir="ltr">mRNA vaccines have become a central part of vaccine research over the last decade due to their application in cancer immunotherapy, and more recently, the rapid response to the SARS-CoV-2 pandemic leading to two clinically approved mRNA vaccines that generate cellular and humoral immunity. These vaccines have saved countless lives and have paved the way for the prevention and treatment of infectious diseases with new mRNA vaccines. One area of ongoing investigation is the longevity and specificity of the adaptive immune response which incorporates both humoral (i.e. antibody) and cellular (T cell) memory. Whilst the focus of the SARS-CoV-2 vaccines was humoral-mediated immunity another emerging field of immunology and vaccine development is the function and generation of tissue-resident memory T(rm) cells. These specialised memory cells reside in tissues awaiting the presence of a pathogen and “raise the alarm” when they encounter the pathogen. This involves the production of inflammatory cytokines that attract other circulating immune cells and have a rapid cytotoxic function that eliminates infected cells. Previous work has shown that the activation of “innate-like” natural killer T (NKT) cells can improve adaptive immune responses, including the production of Trm cells in the liver that can provide sterile protection from malaria sporozoites. This work explored the use of and effect on the adaptive cellular immune system of vaccines comprising NKT cell agonists and mRNA encoding pathogen antigens co-delivered in lipid-delivery vehicles. The inclusion of an NKT cell agonist improved the generation of circulating effector memory CD8+ T(em) cells and the type of ligand affected the magnitude of the priming effector response. Surprisingly, whilst the magnitude of Tem responses generally predicted other memory responses, liver Trm responses were detached from priming responses with regard to specific agonist compounds. In particular, several novel NKT cell agonists, including CI058 generated substantially more liver Trm than the prototypical NKT cell agonist, aGalCer, even though aGalCer induced stronger priming Tem responses. The liver Trm inducing capacity of the novel NKT cell agonists was dependent on modification at the 6’ position of the galactose of a-linked glycolipids. The vaccines developed during this work were able to generate protective liver Trm that could be boosted and protect from Plasmodium sporozoite challenge to model and disease-relevant Plasmodium antigens. Additionally, global research efforts have demonstrated vaccine or infection-acquired immunity (antibody or liver Trm) is impaired by previous red blood cell (RBC) infection by Plasmodium. In contrast, the liver CD8+ Trm cells generated by these NKT cell-adjuvanted mRNA vaccines were unaffected by previous RBC infection. The specific signals from NKT cells that contribute to this improvement in liver Trm formation are unclear, but the response is dependent on both the mRNA vaccine and NKT cell signalling. The response was abrogated in the absence of NKT cells and its magnitude was dependent on a NKT cell phenotype. Modulation of the mRNA component could either impair or improve the overall response and there is synergy between NKT cell and TLR signalling in DC licencing and IL-12 production that positively correlates with liver Trm.</p>

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Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against malaria

Cited by 4 publications

References 0 publications

CD8+ T-cell immunity orchestrated by iNKT cells

CD8+ T-cell immunity orchestrated by iNKT cells

Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

Generation of liver tissue-resident memory T cells with novel NKT cell agonists and mRNA vaccines

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