Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

High levels of circulating GM-CSF+CD4+ T cells are predictive of poor outcomes in sepsis patients: a prospective cohort study

Cellular & Molecular Immunology volume 16, pages 602–610 (2019)Cite this article

Abstract

Granulocyte colony-stimulating factor (GM-CSF), produced by CD4+ T cells, has recently been implicated in the pathogenesis of inflammatory diseases, such as multiple sclerosis and juvenile arthritis. However, the role of GM-CSF-producing CD4+ T cells in sepsis remains unknown. This study reports peripheral changes in GM-CSF-producing CD4+ T cells in septic patients and the possible underlying mechanism by which GM-CSF influences the outcome of sepsis. Forty-three septic patients, 20 SIRS patients, and 20 healthy controls were enrolled in this study and followed for 28 days to assess mortality. We measured the peripheral frequency of GM-CSF+CD4+ T cells and recorded their associated relationship with disease progression. Our data demonstrated that peripheral GM-CSF-producing CD4+ T cells were significantly higher in septic patients than in both SIRS patients and healthy controls. These cells exhibit a memory phenotype and impaired IFN-γ-secreting capacity in sepsis patients. Using a receiver operating curve analysis with 8.01% as a cut-off point, the percentage of GM-CSF+CD4+ T cells could predict the outcome of septic patients. Combined with the increase in GM-CSF-producing CD4+ T cells, inflammatory cytokines IL-1β and IL-6 were also upregulated. Using an in vitro neutrophil model, we found that GM-CSF inhibited C3aR expression, while inducing IL-8 production. Furthermore, this effect was transferrable in plasma from sepsis patients and was attenuated by inhibition of GM-CSF using an anti-GM-CSF antibody. These results indicate that GM-CSF-producing CD4+ T cells may serve as a marker of sepsis severity. Thus, targeting GM-CSF overproduction may benefit sepsis patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Levy, M. M. et al. SCCM/ESICM/ACCP/ATS/SI:2001SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit. Care Med. 31, 1250–1256 (2003).

    Article  Google Scholar 

  2. Balk, R. A. Severe sepsis and septic shock. Crit. Care Clin. 16, 179–192 (2000).

    Article  CAS  Google Scholar 

  3. Van Nieuwenhuijze, A. et al. GM-CSF as a therapeutic target in inflammatory diseases. Mol. Immunol. 56, 675–682 (2013).

    Article  Google Scholar 

  4. Codarri, L. et al. RORγt derives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011).

    Article  CAS  Google Scholar 

  5. EI-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 12, 568–575 (2011).

    Article  Google Scholar 

  6. Meisel, C. et al. Granulocyte–macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression. Am. J. Respir. Crit. Care. Med. 180, 640–648 (2009).

    Article  CAS  Google Scholar 

  7. Orozco, H. et al. Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis. Arch. Surg. 141, 150–153 (2006).

    Article  CAS  Google Scholar 

  8. Xu, R., Lin, F., Bao, C. & Wang, F. S. Mechanism of C5a-induced immunologic derangement in sepsis. Cell Mol. Immunol. 14, 792–793 (2017).

    Article  CAS  Google Scholar 

  9. Burgess, A. W., Camakaris, J. & Metcalf, D. Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J. Biol. Chem. 252, 1998–2003 (1977).

    CAS  PubMed  Google Scholar 

  10. Zhang, J. et al. A novel subset of helper T cells promotes immuneresponses by secreting GM-CSF. Cell Death Differ. 20, 1731–1741 (2013).

    Article  CAS  Google Scholar 

  11. Rasouli, J. et al. Expression of GM-CSF in T cells is increased in multiple sclerosis and suppressed by IFN-β therapy. J. Immunol. 194, 5085–5093 (2015).

    Article  CAS  Google Scholar 

  12. Luken, J. R., Barr, M. J., Chaplin, D. D., Chi, H. & Lanneganti, T. D. Inflammasome-derived IL-1β regulates the production of GM-CSF by CD4(+) T cells and γδT cells. J. Immunol. 188, 3107–3115 (2012).

    Article  Google Scholar 

  13. Hazelzet, J. A. et al. Complement activation in relation to capillary leakage in children with septic shock and purpura. Infect. Immun. 66, 5350–5356 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu, M. C. et al. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proc. Natl. Acad. Sci. USA 110, 9439–9444 (2013).

    Article  CAS  Google Scholar 

  15. Kovach, M. A. & Standiford, T. J. The function of neutrophils in sepsis. Curr. Opin. Infect. Dis. 25, 321–327 (2012).

    Article  CAS  Google Scholar 

  16. Nelson, S. et al. A randomised controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalised patients with community-acquired pneumonia. J. Infect. Dis. 178, 1075–1080 (1998).

    Article  CAS  Google Scholar 

  17. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012).

    Article  CAS  Google Scholar 

  18. Souza-Fonseca-Guimaraes, F., Cavaillon, J. M. & Adib-Conquy, M. Bench-to-bedside review: natural killer cells in sepsis - guilty or not guilty? Crit. Care 17, 235–240 (2013).

    Article  Google Scholar 

  19. Shao, R. et al. Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study. Crit. Care 20, 124–134 (2016).

    Article  Google Scholar 

  20. Drewry, A. M. et al. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit. Care 20, 334–344 (2016).

    Article  Google Scholar 

  21. Singer, M. & Deutschman, C. S. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315, 801–810 (2016).

    Article  CAS  Google Scholar 

  22. Xu, R. et al. Complement 5a receptor –mediated neutrophil dysfunction is associated with a poor outcome in sepsis. Cell Mol Immunol. 13, 103–109 (2016).

    Article  CAS  Google Scholar 

  23. Xu, R. et al. Low expression of CXCR1/2 on neutrophils predicts poor survival in patients with hepatitis B virus-related acutr-on-chronic liver failure. Sci. Rep. 6, 38714–38723 (2016).

    Article  CAS  Google Scholar 

  24. Zhang, J. Y. et al. Interleukin-17–producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 51, 81–91 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We appreciate the cooperation of all septic individuals, SIRS individuals and healthy volunteers who participated in this study. In addition, we would like to thank the native English-speaking scientists of Elixigen Company (Huntington Beach, California) for editing our manuscript. This work was supported by the National Natural Science Foundation of China [grant number 81400626] and the National Natural Science Foundation for innovation group [grant number 81721002].

Author information

Author notes

  1. These authors contributed equally: Huihuang Huang, Siyu Wang, Tianjun Jiang

Authors and Affiliations

  1. Treatment and Research Center for Infectious Disease, Beijing 302 Hospital, Beijing, China

    Huihuang Huang, Siyu Wang, Tianjun Jiang, Rong Fan, Lei Jin, Bo Tu, Bing Song, Chao Zhang, Fu-Sheng Wang & Ruonan Xu

  2. Clinical Research and Management Center, Beijing 302 Hospital, Beijing, China

    Zheng Zhang

  3. Intensive Care Center, Beijing 302 Hospital, Beijing, China

    Jinsong Mu, Ke Li, Yonggang Wang, Fang Lin, Lijian Sun, Biao Xu & Chengcheng Ji

  4. Treatment and Research Center for Liver Failure, Beijing 302 Hospital, Beijing, China

    Jie Xia

  5. Department of Infectious Diseases, The Affiliated Southwest Hospital of the Third Military Medical University, Chongqing, China

    Jing Chen

  6. Medical Department, Army General Hospital of PLA, Beijing, China

    Juan Chang

Authors
  1. Huihuang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianjun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinsong Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yonggang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jie Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lijian Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Biao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chengcheng Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Juan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Bo Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Bing Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Chao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Fu-Sheng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Ruonan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fu-Sheng Wang or Ruonan Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval:

This study was reviewed and approved by the Ethics Committee of Beijing 302 Hospital, China.

Informed consent

Written informed consent was obtained from each subject before recruitment.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Wang, S., Jiang, T. et al. High levels of circulating GM-CSF+CD4+ T cells are predictive of poor outcomes in sepsis patients: a prospective cohort study. Cell Mol Immunol 16, 602–610 (2019). https://doi.org/10.1038/s41423-018-0164-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-018-0164-2

Keywords

This article is cited by

Search

Advanced search

Quick links