Reactive Oxygen Species: Involvement in T Cell Signaling and Metabolism

Franchina, Davide G.; Dostert, Catherine; Brenner, Dirk

doi:10.1016/j.it.2018.01.005

Cited by 256 publications

(202 citation statements)

References 97 publications

(144 reference statements)

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“…In line with our results, blockade of ROS activity by NAC significantly reduced numbers of D‐mannose‐induced Treg cells . Although ROS have been considered toxic products of cellular metabolism, increasing evidence supports the idea that low amounts of ROS are positive contributors to normal signalling pathways . Previous studies demonstrated that ROS further activates Akt/mTOR pathway, enabling optimal T‐cell proliferation and glycolysis .…”

Section: Discussionsupporting

confidence: 90%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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Background Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen‐specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen‐specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results Alum decreases PD‐L1 expression and IL‐10 production induced by PM in human DCs and increases pro‐inflammatory cytokine production. Alum impairs PM‐induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen‐specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM‐activated DCs, impairing their capacity to generate functional Treg cells. Conclusion We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT.

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Section: Discussionsupporting

confidence: 90%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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“…Mitochondrial-derived reactive oxygen species are required for T cell activation and proliferation (9, 10, 51). Therefore, we questioned whether the lower levels of ROS in stimulated SIRT3 deficient T cells directly contributed to their deficient proliferation and activation phenotypes or was an indirect effect of insufficient T cell activation.…”

Section: Resultsmentioning

confidence: 99%

“…To meet the metabolic demands of activation, naïve T cells alter their metabolism by shifting from oxidation of free fatty acids to glycolysis and glutaminolysis (7–10). Specifically, allo-reactive donor T cells demonstrate increased aerobic glycolysi (11, 12), oxidative phosphorylation (OXPHOS)(13), and fatty acid metabolism (14, 15) resulting in increased oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation

Toubai

Tamaki

Peltier

et al. 2018

The Journal of Immunology

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Allogeneic stem cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylases (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Non-mitochondrial class of HDACs regulate T cell responses; but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remain unknown. Herein we report that SIRT3 deficient (SIRT3-/-) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3-/- T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3-/- T cells was associated with a reduction in ROS production which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably the reduction in GVHD in the gastrointestinal (GI) tract was not associated with a substantial reduction in the graft-versus-tumor (GVT) effect. Collectively these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.

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“…Among the changes induced by chronic inflammation and macrophage activation in the tumor microenvironment, oxidative stress plays a key role in negatively affecting the immune response. When ROS is produced excessively, as in chronic inflammation, exceeding the neutralization rate achieved by intracellular antioxidants (mainly glutathione), T cells experience oxidative stress whose persistence may alter their function and blunt effector T‐cell responses . Prolonged oxidative stress can cause different types of DNA damage, triggering genomic instability and transcription errors, leading to failed biosynthetic pathways, compromised proliferation and cell death .…”

Section: Highlighting the Role Of Energy/oxidative Metabolic Changes mentioning

confidence: 99%

Blocking inflammation to improve immunotherapy of advanced cancer

Macciò

Madeddu

2019

Immunology

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The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

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Reactive Oxygen Species: Involvement in T Cell Signaling and Metabolism

Cited by 256 publications

References 97 publications

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation

Blocking inflammation to improve immunotherapy of advanced cancer

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