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

Memory B-cell development is impaired by in vivo blockade of the CD40-CD40 ligand (CD40L) interaction using human Fc immunoglobulin G1 (IgG1)-mouse CD 40 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 CD4 0-Ig-treated mice contain a three- to fourfold higher level of apoptotic ce lls than found in control mice injected with human IgG1 alone. This increas e in apoptosis is not caused by a blockade of the CD40L-mediated rescue sig nal but is the result of an intrinsic defect of GC B cells in CD40-Ig-treat ed mice to receive rescue signals via CD40. While anti-CD40 stimulation mai ntained the viability in culture of GC B cells from control mice, it did no t 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 ligat ion early in the response acid is necessary to allow B-cell rescue from apo ptosis when they subsequently enter the GC.