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

Abstract

Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.

DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

“…44 FL TAM will then favor malignant B-cell growth, by the production of IL-15, 46 B-cell activating factor, 47,48 and DC-SIGN, and through angiogenic and immunosuppressive properties. 26,49 Recently, BCR inhibitors have gained considerable interest because of their effectiveness in several B-cell lymphoma subtypes.…”

IL-15 as a potential target in leukemia

“…Epron et al found that in the presence of CD40L signaling, IL-15 essentially increased B-cell proliferation. 74 These studies demonstrated that the IL-15 signaling pathway plays a role in CLL cell survival and proliferation and that the cooperation between IL-15 and CD40L increased CLL B cell growth.…”

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.…”