Myeloid-Derived Suppressor Cells Mediate Immunosuppression After Cardiopulmonary Bypass. Issue 8 (August 2019)

• Record Type: Journal Article
• Authors: Hübner, Max; Tomasi, Roland; Effinger, David; Wu, Tingting; Klein, Gregor; Bender, Martin; Kilger, Erich; Juchem, Gerd; Schwedhelm, Edzard; Kreth, Simone
• Is Part Of: Critical care medicine. Volume 47:Issue 8(2019)
• Publication Date: 2019-08
• Subjects: adaptive immunity -- arginine -- cardiopulmonary bypass -- immunoparalysis -- myeloid-derived suppressor cells -- T cells; Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000003820
• Languages: English
• ISSNs: 0090-3493

Abstract

Abstract : Objectives: Cardiopulmonary bypass is associated with severe immune dysfunctions. Particularly, a cardiopulmonary bypass–related long-lasting immunosuppressive state predisposes patients to a higher risk of postoperative complications, such as persistent bacterial infections. This study was conducted to elucidate mechanisms of post-cardiopulmonary bypass immunosuppression. Design: In vitro studies with human peripheral blood mononuclear cells. Setting: Cardiosurgical ICU, University Research Laboratory. Patients: Seventy-one patients undergoing cardiac surgery with cardiopulmonary bypass (enrolled May 2017 to August 2018). Interventions: Peripheral blood mononuclear cells before and after cardiopulmonary bypass were analyzed for the expression of immunomodulatory cell markers by real-time quantitative reverse transcription polymerase chain reaction. T cell effector functions were determined by enzyme-linked immunosorbent assay, carboxyfluorescein succinimidyl ester staining, and cytotoxicity assays. Expression of cell surface markers was assessed by flow cytometry. CD15 + cells were depleted by microbead separation. Serum arginine was measured by mass spectrometry. Patient peripheral blood mononuclear cells were incubated in different arginine concentrations, and T cell functions were tested. Measurements and Main Results: After cardiopulmonary bypass, peripheral blood mononuclear cells exhibited significantly reduced levels of costimulatory receptors (inducible T-cell costimulator, interleukin 7 receptor), whereas inhibitory receptors (programmed cell death protein 1 and programmed cell death 1 ligand 1) were induced. T cell effector functions (interferon γ secretion, proliferation, and CD8 + -specific cell lysis) were markedly repressed. In 66 of 71 patients, a not yet described cell population was found, which could be characterized as myeloid-derived suppressor cells. Myeloid-derived suppressor cells are known to impair immune cell functions by expression of the arginine-degrading enzyme arginase-1. Accordingly, we found dramatically increased arginase-1 levels in post-cardiopulmonary bypass peripheral blood mononuclear cells, whereas serum arginine levels were significantly reduced. Depletion of myeloid-derived suppressor cells from post-cardiopulmonary bypass peripheral blood mononuclear cells remarkably improved T cell effector function in vitro. Additionally, in vitro supplementation of arginine enhanced T cell immunocompetence. Conclusions: Cardiopulmonary bypass strongly impairs the adaptive immune system by triggering the accumulation of myeloid-derived suppressor cells. These myeloid-derived suppressor cells induce an immunosuppressive T cell phenotype by increasing serum arginine breakdown. Supplementation with L-arginine may be an effective measure to counteract the onset of immunoparalysis in the setting of cardiopulmonary bypass. Abstract : Supplemental Digital Content is available in the text.