title: Granulocyte colony-stimulating factor impairs CD8(+) T cell functionality by interfering with central activation elements.
abstract: Besides mobilizing stem cells into the periphery, granulocyte colony-stimulating factor (G-CSF) has been shown to influence various types of innate and adaptive immune cells. For example, it impairs the effector function of cytotoxic T lymphocytes (CTLs). It is assumed that this effect is mediated indirectly by monocytes, regulatory T cells and immunomodulatory cytokines influenced by G-CSF. In this study, isolated G-CSF-treated CD8(+) T cells were stimulated antigen-dependently with peptide-major histocompatibility complex (pMHC)-coupled artificial antigen-presenting cells (aAPCs) or stimulated antigen-independently with anti-CD3/CD28 stimulator beads. By measuring the changes in interferon (IFN)-γ and granzyme B expression at the mRNA and protein level, we showed for the first time that G-CSF has a direct effect on CD8(+) CTLs, which was confirmed based on the reduced production of IFN-γ and granzyme B by the cytotoxic T cell line TALL-104 after G-CSF treatment. By investigating further elements affected by G-CSF in CTLs from stem cell donors and untreated controls, we found a decreased phosphorylation of extracellular-regulated kinase (ERK)1/2, lymphocyte-specific protein tyrosine kinase (Lck) and CD3ζ after G-CSF treatment. Additionally, miRNA-155 and activation marker expression levels were reduced. In summary, our results show that G-CSF directly influences the effector function of cytotoxic CD8(+) T cells and affects various elements of T cell activation.
authors.affiliation: Institute for Transfusion Medicine.|Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: C E
authors.initials: CE
authors.lastname: Bunse
authors.affiliation: Institute for Transfusion Medicine.|Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Tischer
authors.affiliation: Institute for Transfusion Medicine.
authors.forename: J
authors.initials: J
authors.lastname: Lahrberg
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Oelke
authors.affiliation: Institute for Transfusion Medicine.
authors.forename: C
authors.initials: C
authors.lastname: Figueiredo
authors.affiliation: Institute for Transfusion Medicine.|Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Blasczyk
authors.affiliation: Institute for Transfusion Medicine.|Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Eiz-Vesper
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C509213:GZMB protein, human; D053804:Granzymes
keywords: G-CSF; T cell activation; antigen-specific T cells; immunotherapy; mobilization