ORCID Profile
0000-0002-6466-5082
Current Organisations
Luxembourg Institute of Health Department of Infection and Immunity
,
University of Luxembourg
,
University of Queensland
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Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.MOLIMM.2017.11.021
Abstract: Natural killer (NK) cells are a critical component in the innate immune response against disease. NK cell function is tightly regulated by specific cytokine and activation/inhibitory receptor signalling, leading to erse effector responses. Like all living cells, energy metabolism is a fundamental requirement for NK cell activation and survival. There is growing evidence that distinct functional profiles of NK cells are determined by alterations to cellular metabolic pathways. In this review, we summarise current literature that has explored NK cell metabolism to provide insight into how metabolic regulation controls NK cell function. We focus on metabolism pathways induced by different NK cell stimuli, metabolic regulatory proteins, and nutrient and hormonal levels in health and disease which impact on NK cell metabolic and functional activity.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2022
DOI: 10.1038/S41467-022-29426-X
Abstract: The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc ), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc -deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency h ers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.
Publisher: Wiley
Date: 09-02-2016
DOI: 10.1038/ICB.2016.9
Abstract: Immunomodulatory therapies can effectively control haematological malignancies by promoting antitumour immunity. Previously, we reported transient growth of poorly immunogenic murine non-Hodgkin B-cell lymphomas (B-NHL) by targeting natural killer T (NKT) cells with a therapeutic vaccine approach. Therapeutic efficacy was highly dependent on the ability of the vaccine to provoke rapid interferon-gamma (IFNγ) production from NKT and NK cells. By manipulating the capacity of either host or lymphoma cells to signal through the IFNγ receptor (IFNγR), we investigated whether the therapeutic effect conferred by vaccine-induced IFNγ is a result of immune cell activation, lymphoma IFNγ sensitivity or a combination of both. We demonstrated that antitumour immunity elicited by vaccination requires IFNγ signalling within host cells but not tumour cells. IFNγR-deficient mice failed to mount an effective antitumour immune response following vaccination despite elevated IFNγ levels. With successive exposure to vaccination, lymphomas acquired an increasingly therapy-resistant phenotype and displayed a reduction in major histocompatibility complex I and CD1d surface expression, which is independent of tumour intrinsic IFNγ signalling. Our results suggest that immunotherapy-induced IFNγ production mainly exerts its therapeutic effect via signalling through host cells, rather than directly to tumour cells in B-NHL. This signifies that intact IFNγ signalling within patients' immune compartment rather than tumour cell sensitivity to IFNγ is more critical for successful treatment. Finally, tumour IFNγ signalling alone does not drive acquired tumour resistance to vaccination, implying that additional immunoediting pathways are responsible for tumour immune escape.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.CMET.2022.04.007
Abstract: Adipose tissue has been linked to inflammation and various physiological processes. In this issue of Cell Metabolism, Caputa et al. describe that perinodal adipocytes adapt their metabolism to actively participate in an immune response against intracellular Listeria monocytogenes.
Publisher: EMBO
Date: 17-01-2022
Publisher: Informa UK Limited
Date: 26-07-2018
Publisher: Elsevier BV
Date: 03-2023
Publisher: American Society of Hematology
Date: 24-12-2020
Abstract: Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6549799
Abstract: Abstract Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8 sup + /sup T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8 sup + /sup dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α sup + /sup DCs to drive efficient cross-priming of antigen-specific CD8 sup + /sup T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α sup + /sup DCs, and polyfunctional CD8 sup + /sup T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8 sup + /sup T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8 sup + /sup T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8 sup + /sup T-cell responses for control of solid tumors. /
Publisher: Informa UK Limited
Date: 07-01-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22542109
Abstract: Supplementary Figures 1-3
Publisher: University of Queensland Library
Date: 2019
Publisher: Informa UK Limited
Date: 18-12-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6549799.V1
Abstract: Abstract Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8 sup + /sup T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8 sup + /sup dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α sup + /sup DCs to drive efficient cross-priming of antigen-specific CD8 sup + /sup T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α sup + /sup DCs, and polyfunctional CD8 sup + /sup T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8 sup + /sup T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8 sup + /sup T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8 sup + /sup T-cell responses for control of solid tumors. /
Publisher: Cold Spring Harbor Laboratory
Date: 07-07-2023
DOI: 10.1101/2023.07.06.547932
Abstract: Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase ( Gclc ), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc -deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection. - GSH-regulated Th17 cell-derived IL-22, but not IL-17 is required to maintain intestinal barrier integrity and to revent lethality following C. rodentium infection. - GCLC expression in IBD patients correlates positively with expression of genes related to gut integrity. - Gclc -deficient Th17 cells accumulate mitochondrial ROS, which is linked to impaired mitochondrial function, ysregulated PI3K/AKT/mTOR signaling and impaired translation of IL-22. - ROS-scavenging, IL-22 reconstitution or T cell-specific expression of IL-22 in Gclc -deficient T cells rescues utant mice from the lethal infection outcome in vivo .
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22542109.V1
Abstract: Supplementary Figures 1-3
Publisher: American Association for Cancer Research (AACR)
Date: 06-2019
DOI: 10.1158/2326-6066.CIR-18-0650
Abstract: Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8+ T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8+ dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α+ DCs to drive efficient cross-priming of antigen-specific CD8+ T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α+ DCs, and polyfunctional CD8+ T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8+ T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8+ T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8+ T-cell responses for control of solid tumors.
Location: Luxembourg
No related grants have been discovered for Takumi Kobayashi.