Mice with a conditional deletion of CD95 in B cells developed splenomegaly and lymphadenopathy with age and died from organ failure caused by massive lymphocyte infiltration. The proliferation of both B and T cells was increased in the mutant mice and both B cells and CD4+ T cells showed evidence of activation (increased expression of MHC class II molecules and inducible T-cell co-stimulator (ICOS), respectively). In addition, B-cell-specific deficiency of CD95 resulted in increased serum levels of interferon-γ (IFNγ), tumour-necrosis factor, interleukin-10 (IL-10) and IL-6, together with a higher number of IL-6-producing B cells and IFNγ-producing T cells.
So, B-cell-specific deficiency of CD95 can induce marked effects on T-cell differentiation and cytokine production. Conversely, the lymphoproliferative disorder in CD95-mutant mice is T-cell dependent; when the CD95-mutant mice were crossed with mice that have few peripheral CD4+ and CD8+ T cells owing to a deficiency of the T-cell receptor β-chain, normal lymphocyte homeostasis was maintained. This indicates that interactions between CD95-deficient B cells and CD95-sufficient T cells drive the immune dysregulation. B-cell–T-cell interactions typically occur in germinal centres, and indeed, mice with a conditional deletion of CD95 specifically in germinal-centre B cells developed a lymphoproliferative disorder that was indistinguishable from that of mice lacking CD95 in all B cells. Deficiency of CD28 — which prevents CD28-mediated co-stimulation of T cells through CD80 on B cells — inhibited the lymphoproliferation in B-cell-specific CD95-deficient mice.
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