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Lymphoma

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

Leukemia volume 26, pages 139–148 (2012)Cite this article

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.

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Acknowledgements

We thank Yannick Jacques (INSERM U892, Nantes) for helpful discussion, Christophe Ruaux for providing tonsil samples, the ‘réseau clinique BREHAT’ as well as the ‘Centre de Ressources Biologiques-Santé’ of Rennes. This work was supported by research grants from the Institut National du Cancer (INCa libre 2005; PL070 and INCa libre 2006; PL06-10), the Association pour le Développement de l′Hémato-Oncologie (ADHO) and the Ligue Régionale Contre le Cancer. GE was supported by a PhD studentship from the Association pour la Recherche contre le Cancer (ARC) and the Société Française d′Hématologie (SFH).

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Authors and Affiliations

  1. INSERM U917, Université Rennes 1, Institut Fédératif de Recherche 140 Génomique Fonctionnelle Agronomie Santé, Rennes, France

    G Epron, P Ame-Thomas, J Le Priol, C Pangault, J Dulong, T Lamy, T Fest & K Tarte

  2. Pôle Cellules & Tissus, CHU Rennes, Rennes, France

    P Ame-Thomas, C Pangault, T Fest & K Tarte

  3. Etablissement Français du Sang, Rennes, France

    J Dulong

  4. Service d′Hématologie Clinique, CHU Rennes, Rennes, France

    T Lamy

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Epron, G., Ame-Thomas, P., Le Priol, J. et al. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling. Leukemia 26, 139–148 (2012). https://doi.org/10.1038/leu.2011.179

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