title: Frequency and functional characterization of exhausted CD8+T cells in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  The phenotypic and functional properties of Tim-3+/PD-1+/CD8+cells as exhausted T cells were investigated in chronic lymphocytic leukemia (CLL).
  
  
  METHODS
  Frequency of CD8+/Tim-3+/PD-1+exhausted cells was determined by flow cytometry. For functional analysis, magnetic beads-isolated CD8+T cells were stimulated with PHA and PMA/ionocymin to assess their proliferative responses and cytokine production by MTT and ELISA, respectively. Cytotoxic activity of isolated CD8+T cells was determined using CD107a degranulation assay.
  
  
  RESULTS
  The proportion of exhausted CD8+T cells was significantly higher in CLL compared to controls. Isolated CD8+T cells from CLL showed functional defects in proliferation, degranulation, and cytokines production. While IL-2, TNF-α, and IFN-γ were significantly lower in CLL patients, IL-10 was higher in the patients group. Patients with progressive clinical stages showed higher frequency and dysfunction of exhausted CD8+T cells.
  
  
  CONCLUSIONS
  Targeting immune inhibitory receptors to restore the function of tumor surrounding T cells could be helpful for immunotherapy of CLL.
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Saeid
authors.identifier: http://orcid.org/0000-0002-8813-6046
authors.initials: S
authors.lastname: Taghiloo
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Allahmoradi
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.|Molecular and Cell-Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Tehrani
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Hadi
authors.initials: H
authors.lastname: Hossein-Nataj
authors.affiliation: Department of Hematology and Oncology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Ramin
authors.initials: R
authors.lastname: Shekarriz
authors.affiliation: Department of Hematology and Oncology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Ghasem
authors.initials: G
authors.lastname: Janbabaei
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.|Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Saeid
authors.initials: S
authors.lastname: Abediankenari
authors.affiliation: Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.|Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Asgarian-Omran
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D017635:Clonal Anergy / Q000235:genetics*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D015759:Ionomycin / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000494:pharmacology; D061251:Primary Cell Culture; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D015415:Biomarkers; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C573415:IFNG protein, human; C508609:IL10 protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D010835:Phytohemagglutinins; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015759:Ionomycin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate
keywords: PD-1; Tim-3; chronic lymphocytic leukemia; exhausted T cells