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Published on: June 12, 2021
Frequency and functional characterization of exhausted CD8+ T cells in chronic lymphocytic leukemia
Saeid Taghiloo1, Esmaeil Allahmoradi1, Mohsen Tehrani1,2
1Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Insights
Exhausted CD8+ T cells are more frequent and dysfunctional in chronic lymphocytic leukemia (CLL), impacting immune response. Restoring T cell function via immune checkpoint inhibitors may improve CLL immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation.
- T cell exhaustion, marked by inhibitory receptors like Tim-3 and PD-1, is implicated in cancer progression.
Purpose of the Study:
- To investigate the phenotypic and functional characteristics of exhausted CD8+ T cells in CLL patients.
- To correlate the frequency and dysfunction of these cells with clinical progression in CLL.
Main Methods:
- Flow cytometry was used to quantify CD8+ Tim-3+ PD-1+ exhausted T cells.
- Functional assays included proliferation (MTT), cytokine production (ELISA), and cytotoxic activity (CD107a degranulation assay).
Main Results:
- CLL patients exhibited a significantly higher proportion of exhausted CD8+ T cells compared to controls.
- These cells displayed impaired proliferation, degranulation, and reduced production of IL-2, TNF-α, and IFN-γ, with elevated IL-10.
- Progressive CLL stages correlated with increased frequency and dysfunction of exhausted CD8+ T cells.
Conclusions:
- Exhausted CD8+ T cells play a significant role in the immune pathology of CLL.
- Targeting immune inhibitory receptors could restore T cell function and enhance immunotherapy efficacy in 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.
