Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ

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Abstract
Protein kinase C (PKC), which comprises 11 closely related isoforms, has been implicated in a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis and tumour development1,2,3,4. Among the PKC isotypes, PKC-δ is unique in that its overexpression results in inhibition of cell growth5,6,7,8,9,10,11. Here we show that mice that lack PKC-δ exhibit expansion of the B-lymphocyte population with the formation of numerous germinal centres in the absence of stimulation. The rate of proliferation in response to stimulation was greater for B cells from PKC-δ-deficient mice than for those from wild-type mice. Adoptive transfer experiments suggested that the hyperproliferation phenotype is B-cell autonomous. Production of interleukin-6 was markedly increased in B cells of PKC-δ-null mice as a result of an increase in the DNA-binding activity of NF-IL6. Furthermore, the PKC-δ-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs. These results suggest that PKC-δ has an indispensable function in negative regulation of B-cell proliferation, and is particularly important for the establishment of B-cell tolerance.