Rewiring of CD40 is necessary for delivery of rescue signals to B cells in germinal 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 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.
Siepmann
K
K
Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Skok
J
J
van Essen
D
D
Harnett
M
M
Gray
D
D
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007156:Immunologic Memory; D020287:In Situ Nick-End Labeling; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3
D019013:CD40 Antigens; D007074:Immunoglobulin G; D011506:Proteins; D048008:TNF Receptor-Associated Factor 3; D023201:CD40 Ligand