Il-21 And Cd40l Signals From Autologous T Cells Can Induce Antigen-Independent Proliferation Of Chronic Lymphocytic Leukemia Cells

Abstract Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. While it is well established that monoclonal malignant B cells multiply in secondary lymphoid tissue, the mechanisms leading to their proliferation are still uncertain. In addition to BCR-triggered signals, other microenvironmental factors might well be involved. In proliferation centres, leukemic B cells are in close contact with CD4+CD40L+ T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We next determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. Then, we defined an IL-21-induced gene signature in CLL, containing components of JAK/STAT and apoptosis pathways in addition to the previously described Granzyme B (GZMB) expression. This signature could subsequently be detected in LN samples from CLL patients. Finally, we demonstrated presence of IL-21 RNA and protein in LN samples from patients. These results indicate that, in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40L and IL-21. Targeting this interaction might offer new venues to the treatment of CLL.