The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Abstract

The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common ␥ chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and pre- IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in adults, is characterized by the progressive accumulation of CD5 ϩ neoplastic B cells, 1-3 which results from a dynamic balance between cell death and proliferation. 3,4 The finding that purified CLL cells do not proliferate and tend to undergo spontaneous apoptosis in vitro suggests that factors inducing CLL cell survival and proliferation might be present in the microenvironment of lymphoid organs or of the bone marrow. 5,6 Several cytokines such as the TNF family members BAFF and APRIL, 7,8 the chemokine SDF-1, 9,10 and interleukin-2 (IL-2) 11,12 and IL-15 13 stimulate CLL cell proliferation and/or survival in vitro. IL-2 and IL-15 share the usage of the IL-2R␤ (CD122) and of the common ␥ chain (␥ c ; CD132) 14,15 and thus have similar functional effects on IL-2R␤/␥ c ϩ cells. 16,17 The IL-2R␤ and ␥ c chains signal through the JAK1 and JAK3 tyrosine kinases, which activate downstream STAT pathways. 18,19 In addition to the IL-2R␤/␥ c complex, specific 21 molecules are required for high-affinity binding of each cytokine. Unlike IL-2R␣, IL-15R␣ is a high-affinity receptor also when expressed as an isolated chain, and is present on both lymphoid and nonlymphoid cell types. 20,21 IL-15R␣ is crucial for IL-15 activity, since both IL-15-and IL-15R␣-deficient mice display similar defects in the development of natural killer (NK) cells, of intraepithelial T lymphocytes, and of CD8 ϩ memory-type T cells. 22,23 IL-15 gene is expressed in several tissues, and IL-15 can be either secreted in low amounts or displayed as a membrane-bound cytokine by several cell types. [24][25][26][27][28] Therefore IL-15 is considered a microenvironmental factor, which supports lymphoid cell homeostasis and survival. 29-31 IL-15 is a growth or survival factor not only for CLL cells 13 but also for cells of other lymphoid neoplasias, 32-34 at least in vitro. Moreover, in IL-15-transgenic mice, IL-15 overexpression induces fatal T or NK lymphoproliferative disorders. 35 We and others recently demonstrated that IL-21, the last identified member of the IL-2 family, 36-38 is unable to trigger CLL cell proliferation, but rather induces their apoptosis. 39,40 This effect is potentiated by cell activation with CD40L, 39 with CpG synthetic oligonucleotides, or by BCR cross-linking. 40 IL-21 induces the JAK1 and JAK3 and the STAT1, STAT3, and STAT5 tyrosine phosphorylation in CLL B cells. 39 Similar early signaling events are also activated by IL-21, IL-2, or IL-1...

Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

“…IL-15Ra is poorly expressed in the absence of stimulation in B cells from hematological diseases and is upregulated by in vitro stimulation with CD40L (11,35). In random CLL samples, fluorescent rhIL-15 binds B leukemic cells, and this is decreased significantly in the presence of a blocking IL-15Ra mAb (Fig.…”

“…These included hematological pathologies, such as chronic lymphocytic leukemia (CLL), in which recombinant human IL-15 (rhIL-15) sustains the survival of leukemic cells in vitro (11).…”

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

“…32 Our detailed analysis of CD40L-and IL-15-driven signals provides clues to their respective roles in normal B cell behavior. Intriguingly, our study provides evidence that the observed synergy between IL-15 and CD40L in normal and FL B cells is based on a different mechanism from that reported in CLL B cells, which involved an 19 We demonstrated for the first time that CD40L drives an increase in the expression of total STAT5 in tonsil B cells. This unexpected result corroborates with the identification of a small population of activated tonsil GC B cells displaying an increased expression of total STAT5 and committed to memory cell fate.…”

“…The increased sensitivity of CD40-activated B-CLL cells to mitogenic effects of IL-15 was previously associated with an increased expression of IL-15Ra and IL-2Rb. 19 However, the level of IL-15Ra was not affected by CD40 triggering in normal B cells at both mRNA and protein levels. In addition, the faint upregulation of IL-2Rb and IL-2Rg was associated with a very limited increase in their capacity to bind exogenous IL-15 (Supplementary Figure S4).…”

“…In particular, paracrine IL-15 sustains survival and proliferation of chronic lymphocytic leukemia (CLL) B cells through a strong activation of both STAT5 and ERK1/2 pathways. 18,19 Interestingly, the mitogenic and anti-apoptotic effects of IL-15 are enhanced when CLL B cells are pre-activated by CD40. These results are particularly relevant when considering that CLL cells, like FL cells, are strongly dependent on a specific microenvironment including CD4 pos T cells, stromal cells and myeloid cells.…”