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CD154 Tone Sets the Signaling Pathways and Transcriptome Generated in Model CD40-Pluricompetent L3055 Burkitt’s Lymphoma Cells¹

Ross Stewart^*, Wenbin Wei^2,, Anita Challa^2,*, Richard J. Armitage, John R. Arrand, Martin Rowe, Lawrence S. Young, Aristides Eliopoulos and John Gordon^3,*

^* MRC Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom; Cancer Research United Kingdom, Institute for Cancer Studies, University of Birmingham Medical School, Birmingham, United Kingdom; and Inflammation Research, Amgen, Seattle, WA 98101

Activated B cells reacting to small amounts of CD40L (CD154) maintain homeostasis by suppressing default apoptosis. Additional outcomes, particularly differentiation, demand higher CD40 occupancy. Here, focusing on survival, we compared changes in the transcriptome of pleiotropically competent, early passage L3055 Burkitt’s lymphoma cells confronted with low (picomolar) and high (nanomolar) concentrations of CD154 to gain insight into how a single receptor sets these distinct phenotypes. Of 267 genes altering transcriptional activity in response to strong CD154 tone, only 25 changed coordinately on low receptor occupancy. Seven of the top nine common up-regulated genes were targets of NF-B. Direct measurement and functional inhibition of the NF-B pathway revealed it to be central to a CD40-dependent survival signature. Although the canonical NF-B axis was engaged by both signaling strengths equally, robust alternative pathway activation was a feature selective to a strong CD40 signal. Discriminatory exploitation of the two separate arms of NF-B activation may indicate a principle whereby a cell senses and reacts differentially to shifting ligand availability. Identifying components selectively coupling CD40 to each axis could indicate targets for disruption in B cell pathologies underpinned by ectopic and/or hyper-CD154 activity such as neoplasia and some autoimmunities.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Medical Research Council (U.K.), Cancer Research U.K., and the Leukaemia Research Fund.

² W.W. and A.C. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. John Gordon, Medical Research Council Centre for Immune Regulation, Division of Immunity and Infection, The Medical School, Vincent Drive, Birmingham, United Kingdom. E-mail address: j.gordon{at}bham.ac.uk

⁴ Abbreviations used in this paper: GC, germinal center; BL, Burkitt’s lymphoma; sCD154, recombinant soluble trimeric human CD40L; cIAP2, cellular inhibitor of apoptosis protein.