Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair.

Abstract

Myeloid-derived suppressor cells (MDSCs) have the capacity to suppress T-cell-mediated immune responses and impact the clinical outcome of cancer, infections, and transplantation settings. Although MDSCs were initially described as bone marrow-derived immature myeloid cells (either monocytic or granulocytic MDSCs), mature neutrophils have been shown to exert MDSC activity toward T cells in ways that remain unclear. In this study, we demonstrated that human neutrophils from both healthy donors and cancer patients do not exert MDSC activity unless they are activated. By using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent interactions between neutrophils and T cells. In addition to these cellular interactions, neutrophils are engaged in the uptake of pieces of T-cell membrane, a process called trogocytosis. Together, these interactions led to changes in T-cell morphology, mitochondrial dysfunction, and adenosine triphosphate depletion, as indicated by electron microscopy, mass spectrometry, and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T-cell nonresponsiveness and irreparable cell damage.

• Authors: Cathelijn E M Aarts, Ida H Hiemstra, Eelke P Béguin, Arjan J Hoogendijk, Souhailla Bouchmal, Michel van Houdt, Anton T J Tool, Erik Mul, Machiel H Jansen, Hans Janssen, Floris P J van Alphen, Jan-Paul de Boer, Charlotte L Zuur, Alexander B Meijer, Timo K van den Berg, Taco W Kuijpers
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 22 Pg. 3562-3574 (11 26 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 31738831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Biomarkers
• Cytokines
• Reactive Oxygen Species

Topics

• Apoptosis
• Biomarkers
• Cell Communication (immunology)
• Cell Degranulation (immunology)
• Cytokines (metabolism)
• Humans
• Immunomodulation
• Immunophenotyping
• Lymphocyte Activation (immunology)
• Myeloid-Derived Suppressor Cells (immunology, metabolism)
• Neutrophil Activation (immunology)
• Neutrophils (immunology, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• T-Lymphocytes (immunology, metabolism)