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

Darcy, Christabelle J., Minigo, Gabriela, Piera, Kim A., Davis, Joshua S., McNeil, Yvette R., Chen, Youwei, Volkheimer, Alicia D., Weinberg, J. Brice, Anstey, Nicholas M. and Woodberry, Tonia (2014). Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Critical Care,18(4 - Article No. R163).

Document type: Journal Article
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IRMA ID 84473293xPUB10
NHMRC Grant No. 496600
Title Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients
Author Darcy, Christabelle J.
Minigo, Gabriela
Piera, Kim A.
Davis, Joshua S.
McNeil, Yvette R.
Chen, Youwei
Volkheimer, Alicia D.
Weinberg, J. Brice
Anstey, Nicholas M.
Woodberry, Tonia
Journal Name Critical Care
Publication Date 2014
Volume Number 18
Issue Number 4 - Article No. R163
ISSN 1364-8535   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84907420706
Total Pages 12
Place of Publication United Kingdom
Publisher BioMed Central Ltd.
HERDC Category C1 - Journal Article (DIISR)
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.
DOI http://dx.doi.org/10.1186/cc14003   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au


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