CD4+ T Cells are Exhausted and Show Functional Defects in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. This health problem is caused due to the accumulation of mature B-lymphocytes in the peripheral blood and bone marrow. In the course of cancer, CD4+ T cells become "exhausted" and characterized with poor effector functions and the expression of multiple inhibitory receptors.

To investigate the frequency and functional properties of exhausted CD4+ T lymphocytes in patients with CLL.

Peripheral blood mononuclear cells were obtained from 25 untreated CLL patients and 15 healthy volunteers. CLL patients were clinically classified according to the Rai staging system. The frequency of CD4+/Tim-3+/PD-1+ cells was obtained by flow cytometry. To evaluate cell proliferation and cytokine production, CD4+ T cells were isolated and stimulated with phytohemagglutinin and PMA/ionomycin. Concentrations of IL-2, IFN-γ, TNF-α, and IL-10 were measured in the culture supernatants of stimulated cells by the ELISA technique.

The percentage of CD4+/Tim-3+/PD-1+ cells was significantly higher in CLL patients than that of healthy controls. CD4+ T cells from CLL patients showed lower proliferative responses, a lower production of IL-2, IFN-γ, and TNF-α, and a higher production of IL-10, compared to healthy controls. CD4+ T cells from CLL patients in advanced clinical stages showed more exhaustion features than those of early stages.

Given that the exhaustion phase of T cells can be reversible, targeted blocking of immune inhibitory molecules could be a promising tool to restore the host immune responses against leukemic cells in CLL.