title: 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.
authors.affiliation: INSERM U917, Université Rennes 1, Institut Fédératif de Recherche 140 Génomique Fonctionnelle Agronomie Santé, Rennes, France.
authors.forename: G
authors.initials: G
authors.lastname: Epron
authors.forename: P
authors.initials: P
authors.lastname: Ame-Thomas
authors.forename: J
authors.initials: J
authors.lastname: Le Priol
authors.forename: C
authors.initials: C
authors.lastname: Pangault
authors.forename: J
authors.initials: J
authors.lastname: Dulong
authors.forename: T
authors.initials: T
authors.lastname: Lamy
authors.forename: T
authors.initials: T
authors.lastname: Fest
authors.forename: K
authors.initials: K
authors.lastname: Tarte
mesh_terms: D017209:Apoptosis; D023201:CD40 Ligand / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000276:immunology / Q000473:pathology*; D009000:Monocytes / Q000166:cytology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D019409:Interleukin-15; D023201:CD40 Ligand