Activation-induced Traf3 alternative splicing controls the non-canonical NFkB pathway and chemokine expression in human T cells [Immunology]

March 26th, 2014 by Michel, M., Wilhelmi, I., Schultz, A.-S., Preussner, M., Heyd, F.

The non-canonical nuclear factor kappa B (ncNFkB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. While ncNFkB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remains largely unexplored. ncNFkB activity critically depends on the upstream NFkB inducing kinase (NIK). NIK expression is negatively regulated by the full-length isoform of TNF receptor-associated factor 3 (Traf3) as formation of a NIK-Traf3-Traf2 complex targets NIK for degradation. Here we show that T cell specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) that, in contrast to the full-length protein, activates ncNFkB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFkB signaling in activated T cells. ncNFkB activity results in expression of several chemokines, among them B-cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4+ T cells. As CxCL13 plays an important role in B cell migration and activation, our data suggest an involvement and provide a mechanistic basis for Traf3 alternative splicing and ncNFkB activation in contributing to T cell dependent adaptive immunity.