Rosa Visone
G. D’Annunzio University, Italy
Title: MiR-181b in B cells of chronic lymphocytic leukemia is regulated by cellular interaction with CD4+ T cells and increases the CTL toxicity versus the leukemic clone
Biography
Biography: Rosa Visone
Abstract
Statement of the Problem: Clinical progression of chronic lymphocytic leukemia (CLL) is characterized by immune cell dysfunction due, at least in part, to T cell defects, such as decreased expression of CD40L and reduced signaling via the TCR CD3. This compromise the ability of T cells to respond and to eliminate leukemic cell from CLL patients. Changes in microRNAs expression also characterize clinical progression of CLL with a strong decrease of miR-181b/a and miR-130a associated with the more aggressive phase of the disease. The miR-181b targets anti apoptotic proteins, such as BCL-2 and MCL1.
Aim: The purpose of this study is to find how these microRNAs are deregulated in CLL and if they are involved in the immune escape that characterize this disease.
Methodology & Findings: We co-cultured pure CLL-B cells with either activated (CD2, CD3 and CD28 antibodies, used to mimic antigen-presenting cells) or non-activated CD4+ T cells from healthy donors or from PBMC of CLL patients. We observed a significant increase of miR-181b and miR-130a expression in CLL B-cells after co-culture with activated CD4+ T cells. By the use of specific antibodies, we established that this effect is a T/B contact-dependent signaling mediated through CD40L-CD40 interaction. We determine that increased expression of the 3 miRs occurs at the transcriptional level. In this context, miR-181b enhanced the maturation and activity of cytotoxic T cells and consequently, the apoptotic response of CLL cells. This phenomenon was due, at least in part, to miR-181b-induced depletion of interleukin 10, which is a strong inhibitor of the immune response in CLL. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b induces the death of CLL cells in vivo only when functional T cells are restored.
Conclusion & Significance: In conclusion, we demonstrate that the down-regulation of miR-181b in CLL cells is involved in the immune dysfunction that characterizes this disease. Restoration of physiological miR-181b activity in B CLL cells may be a challenging novel approach to the treatment of CLL patients.