Rewiring of CD40 is necessary for delivery of rescue signals to B cells in germinal centres and subsequent entry into the memory pool

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Abstract
Memory B‐cell development is impaired by in vivo blockade of the CD40–CD40 ligand (CD40L) interaction using human Fc immunoglobulin G1 (IgG1)‐mouse CD40 fusion protein (CD40‐Ig); however, germinal centre (GC) formation is not. We show here that the block in B‐cell differentiation in these mice is at the stage of rescue from apoptosis and exit from the GC. Thus, GC from CD40‐Ig‐treated mice contain a three‐ to fourfold higher level of apoptotic cells than found in control mice injected with human IgG1 alone. This increase in apoptosis is not caused by a blockade of the CD40L‐mediated rescue signal but is the result of an intrinsic defect of GC B cells in CD40‐Ig‐treated mice to receive rescue signals via CD40. While anti‐CD40 stimulation maintained the viability in culture of GC B cells from control mice, it did not rescue GC B cells from CD40‐Ig‐treated mice. This data is consistent with the notion that a ‘rewiring’ of the CD40 molecule is induced by CD40 ligation early in the response and is necessary to allow B‐cell rescue from apoptosis when they subsequently enter the GC.