Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents

Minns, Danielle; Smith, Katie J; Findlay, Emily Gwyer

doi:10.1155/2019/8968943

Cited by 54 publications

(49 citation statements)

References 169 publications

(165 reference statements)

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“…The regulation of the innate and adaptive immune systems by neutrophils has been reviewed extensively . Neutrophil granule contents participate in many regulatory activities, including those involving T cells, dendritic cells, B cells, and monocytes . The interaction between neutrophils and monocytes is particularly relevant to antimicrobial activity and inflammatory diseases.…”

Section: Role Of Exocytosis In Neutrophil Functionmentioning

confidence: 99%

“…[70][71][72][73][74][75][76][77][78][79] Neutrophil granule contents participate in many regulatory activities, including those involving T cells, dendritic cells, B cells, and monocytes. 70,72,73,80 The interaction between neutrophils and monocytes is particularly relevant to antimicrobial activity and inflammatory diseases. Neutrophil granule mobilization alters monocyte adhesion, migration, and bacterial phagocytosis and killing.…”

Section: Role Of Exocytosis In Neutrophil Functionmentioning

confidence: 99%

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Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil‐mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.

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Section: Role Of Exocytosis In Neutrophil Functionmentioning

confidence: 99%

Section: Role Of Exocytosis In Neutrophil Functionmentioning

confidence: 99%

Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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“…However, in other scenario were endogenous MPO is not an autoantigen (like collagen-induced arthritis, pristine-induced lupus nephritis or healthy donors) MPO attenuates or even suppresses T cells responses, including decreased proliferation of human T cells in vitro (44), lower DC activation and migration, showing an increased proliferation, activation and proin ammatory cytokine production in MPO −/− mice (6). These differentiation of responses may depend of unusual mechanisms driven by MPO (45), making clear that the context in which the immune response is mounted, matters.…”

Section: Discussionmentioning

confidence: 99%

Conformational changes in myeloperoxidase induced by ubiquitin and NETs containing free ISG15 from Systemic Lupus Erythematosus patients promotes a pro-inflammatory cytokine response in CD4+ T cells.

Carrillo-Vázquez

Jardón-Valadez

Torres-Ruíz

et al. 2020

Preprint

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Background: Neutrophil extracellular traps (NETs) from patients with Systemic Lupus Erythematosus (SLE) are characterized by lower ubiquitylation and myeloperoxidase (MPO) as a substrate. The structural and functional effect of such modification and if there are additional post-translational modifications (PTMs) are unknown. Methods: To assess the expression and functional role of PTMs in NETs of patients with SLE; reactivation, proliferation and cytokine production was evaluated by flow cytometry using co-cultures with dendritic cells (DC) and CD4+ from SLE patients and healthy controls. The impact of ubiquitylation on MPO was assessed by molecular dynamics. The expression of ISG15 in NETs was evaluated by immunofluorescence and Western Blot. Results: Fifteen patients with SLE and 10 healthy controls were included. In the co-cultures of CD4+ lymphocytes with DC stimulated with ubiquitylated MPO or recombinant MPO, a higher expression of IFNγ and IL17A was found in CD4+ from SLE patients (p<0.05). Furthermore, with DC stimulated with ubiquitylated MPO a trend towards increased expression of CD25 and Ki67 was found in lupus CD4+ lymphocytes, while the opposite was documented in controls (p<0.05). Through molecular dynamics we found the K129-K488-K505 residues of MPO as susceptible to ubiquitylation. Ubiquitylation affects the hydration status of the HEME group depending on the residue to which it is conjugated. R239 was found near by the HEME group when the ubiquitin was in K488-K505. In addition, we found greater expression of ISG15 in the SLE NETs vs controls (p<0.05), colocalization with H2B (r=0.78) only in SLE samples and increased production of IFNγ in PBMCs stimulated with lupus NETs compared to healthy controls NETs. Conclusion: The ubiquitylated MPO has a differential effect on the induction of reactivation of CD4+ lymphocytes in patients with SLE, which may be related to structural changes by ubiquitylation at the catalytic site of MPO. Besides a lower ubiquitylation pattern, NETs of patients with SLE are characterized by the expression of ISG15, and the induction of IFNγ by Th1 cells.

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“…In addition, neutrophils release various pro-inflammatory mediators, e.g., cytokines and granule contents, that may impact on the development of adaptive anticancer immunity [as reviewed by [ 231 ]. For instance, the release of human neutrophil peptides, lactoferrin, α-defensins, and LL-37 are generally reported as having an activating effect on T cell immunity, whereby lactoferrin promotes the recruitment and activation of APCs [ 232 ] and α-defensins dose-dependently attract monocytes [ 233 ] and promote DC and T cell infiltration [ 234 ].…”

Section: Neutrophil-mediated Induction Of Adaptive Anticancer Immumentioning

confidence: 99%

The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer

Avtenyuk

Visser

Bremer

et al. 2020

IJMS

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The advent of immunotherapy has had a major impact on the outcome and overall survival in many types of cancer. Current immunotherapeutic strategies typically aim to (re)activate anticancer T cell immunity, although the targeting of macrophage-mediated anticancer innate immunity has also emerged in recent years. Neutrophils, although comprising ≈ 60% of all white blood cells in the circulation, are still largely overlooked in this respect. Nevertheless, neutrophils have evident anticancer activity and can induce phagocytosis, trogocytosis, as well as the direct cytotoxic elimination of cancer cells. Furthermore, therapeutic tumor-targeting monoclonal antibodies trigger anticancer immune responses through all innate Fc-receptor expressing cells, including neutrophils. Indeed, the depletion of neutrophils strongly reduced the efficacy of monoclonal antibody treatment and increased tumor progression in various preclinical studies. In addition, the infusion of neutrophils in murine cancer models reduced tumor progression. However, evidence on the anticancer effects of neutrophils is fragmentary and mostly obtained in in vitro assays or murine models with reports on anticancer neutrophil activity in humans lagging behind. In this review, we aim to give an overview of the available knowledge of anticancer activity by neutrophils. Furthermore, we will describe strategies being explored for the therapeutic activation of anticancer neutrophil activity.

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Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents

Cited by 54 publications

References 169 publications

Therapeutic targeting of neutrophil exocytosis

Therapeutic targeting of neutrophil exocytosis

Conformational changes in myeloperoxidase induced by ubiquitin and NETs containing free ISG15 from Systemic Lupus Erythematosus patients promotes a pro-inflammatory cytokine response in CD4+ T cells.

The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer

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