Saeid Taghiloo1, Esmaeil Allahmoradi1, Mohsen Tehrani1,2, Hadi Hossein-Nataj1, Ramin Shekarriz3, Ghasem Janbabaei3, Saeid Abediankenari1,4, Hossein Asgarian-Omran1,4. 1. Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. 2. Molecular and Cell-Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran. 3. Department of Hematology and Oncology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran. 4. Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Abstract
OBJECTIVES: 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. CONCLUSION: Targeting immune inhibitory receptors to restore the function of tumor surrounding T cells could be helpful for immunotherapy of CLL.
OBJECTIVES: 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. CONCLUSION: Targeting immune inhibitory receptors to restore the function of tumor surrounding T cells could be helpful for immunotherapy of CLL.
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