Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients

Christabelle Darcy, Gabriela Minigo, Kim Piera, Joshua Davis, Yvette McNeil, Youwei Chen, Alicia Volkheimer, J Brice Weinberg, Nicholas Anstey, Tonia Woodberry

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    Abstract

    Introduction: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis.

    Methods: Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated.

    Results: Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock there
    was a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function.

    Conclusions: For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3
    zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets for
    novel adjunctive therapies in sepsis.
    Original languageEnglish
    Pages (from-to)1-12
    Number of pages12
    JournalCritical Care
    Volume18
    Issue number4
    DOIs
    Publication statusPublished - 2014

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    Septic Shock
    Arginine
    Sepsis
    Neutrophils
    T-Lymphocytes
    Interphase
    Arginase
    Cell Proliferation
    Ficoll
    Specific Gravity
    T-Cell Antigen Receptor
    Tertiary Care Centers
    Communicable Diseases
    Interleukin-6
    Flow Cytometry
    Cell Culture Techniques
    High Pressure Liquid Chromatography

    Cite this

    Darcy, Christabelle ; Minigo, Gabriela ; Piera, Kim ; Davis, Joshua ; McNeil, Yvette ; Chen, Youwei ; Volkheimer, Alicia ; Weinberg, J Brice ; Anstey, Nicholas ; Woodberry, Tonia. / Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. In: Critical Care. 2014 ; Vol. 18, No. 4. pp. 1-12.
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    title = "Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients",
    abstract = "Introduction: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis.Methods: Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated.Results: Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock therewas a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function.Conclusions: For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets fornovel adjunctive therapies in sepsis.",
    author = "Christabelle Darcy and Gabriela Minigo and Kim Piera and Joshua Davis and Yvette McNeil and Youwei Chen and Alicia Volkheimer and Weinberg, {J Brice} and Nicholas Anstey and Tonia Woodberry",
    year = "2014",
    doi = "10.1186/cc14003",
    language = "English",
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    Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. / Darcy, Christabelle; Minigo, Gabriela; Piera, Kim; Davis, Joshua; McNeil, Yvette; Chen, Youwei; Volkheimer, Alicia; Weinberg, J Brice; Anstey, Nicholas; Woodberry, Tonia.

    In: Critical Care, Vol. 18, No. 4, 2014, p. 1-12.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients

    AU - Darcy, Christabelle

    AU - Minigo, Gabriela

    AU - Piera, Kim

    AU - Davis, Joshua

    AU - McNeil, Yvette

    AU - Chen, Youwei

    AU - Volkheimer, Alicia

    AU - Weinberg, J Brice

    AU - Anstey, Nicholas

    AU - Woodberry, Tonia

    PY - 2014

    Y1 - 2014

    N2 - Introduction: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis.Methods: Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated.Results: Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock therewas a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function.Conclusions: For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets fornovel adjunctive therapies in sepsis.

    AB - Introduction: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis.Methods: Using flow cytometry, cell culture, HPLC, arginase activity and mRNA detection, our study examined whether neutrophils, with reduced buoyant density isolated in the Ficoll interface, metabolise L-arginine and suppress T cell proliferation in sepsis. A total of 35 sepsis patients (23 with septic shock) and 12 hospital controls in a tertiary referral hospital in tropical Australia were evaluated.Results: Only sepsis patients had interphase neutrophils, neutrophils co-purifying with mononuclear cells (≤1.077 specific gravity). The percentage of interphase neutrophils in sepsis was proportional to sepsis severity and correlated with plasma IL-6 concentrations. Ex vivo, sepsis-derived interphase neutrophils expressed arginase, metabolised culture L-arginine and suppressed T cell proliferation and CD3 zeta-chain expression. In vivo, in septic shock therewas a longitudinal inverse association between interphase neutrophil number and CD3 zeta-chain expression. Depletion or inhibition of interphase neutrophils in vitro restored zeta-chain expression and T cell function.Conclusions: For the first time during an acute human infection, interphase neutrophils that express arginase were found to circulate in sepsis, in proportion to disease severity. These neutrophil-MDSCs impair T cell CD3zeta-chain expression and T cell function via L-arginine metabolism, and likely contribute to the T cell dysfunction seen in sepsis. Modulation of neutrophil-MDSC or their downstream effects warrant consideration as targets fornovel adjunctive therapies in sepsis.

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    U2 - 10.1186/cc14003

    DO - 10.1186/cc14003

    M3 - Article

    VL - 18

    SP - 1

    EP - 12

    JO - Critical Care

    JF - Critical Care

    SN - 1364-8535

    IS - 4

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