Interactions between LMP1 and CD40 signals (34.15)

Abstract

Abstract The EBV encoded protein LMP1 signals to B lymphocytes in a manner similar in many respects to the normal cellular protein CD40. Under circumstances in which LMP1, not expressed in normal latency, is re-expressed in vivo, LMP1 and CD40 are expressed in the same cells. Thus, we have used both cell line and transgenic mouse models to investigate the interaction of LMP1 and CD40 signals. CD40 and LMP1 signals cooperate in stimulation of JNK , IkBa and p38 MAPK phosphorylation in B cell lines, as well as in primary mouse B cells and BMDCs, though TRAFs 2 and 3 are degraded in a manner similar to CD40 signaling alone. Though additivity is seen in early signaling through these two pathways, in vivo effects of LMP1 + CD40 signaling do not always show cooperation. Expression of a hybrid molecule with the extracellular domain of mouse CD40 and the intracellular signaling domain of LMP1 in B cells, macrophages and dendritic cells on a CD40 negative background leads to lymphadenopathy, splenomegaly, spontaneous germinal centers, and autoantibody formation. However, when CD40 is also expressed some of these in vivo effects are ameliorated (splenomegaly, some cytokines), or delayed (autoantibody production). One interesting effect of mCD40-LMP1 signaling in vivo is elevated serum IL17, which we hypothesized is secondary to elevated IL6 production in the mCD40-LMP1tg mice. However, mice expressing both mCD40-LMP1 and mCD40 transgenes also have elevated IL6, but serum IL17 levels are not elevated, suggesting that other factors or pathways are involved.