Defining a novel role for the NF-κB pathway in proximal TCR signaling. (IRM10P.746)

Abstract

Abstract In the accepted model of T cell activation, parallel and independent signal transduction pathways activate the transcription factors NF-κB, NFAT and AP-1 to drive clonal expansion of T cells in response to antigen. Surprisingly, we found that CD8 T cells lacking NF-κB subunits p50 and cRel fail to activate NFAT contributing to their severely impaired in vivo responsiveness. We further demonstrated that attenuated NFAT activation was due to diminished Calcium influx upon TCR engagement, and that this reduction was accomplished via sub-par phosphorylation of PLCγ. The functional relevance of impaired PLCγ activation was demonstrated by rescue of p50-/-cRel-/- T cell proliferation through pharmacological initiation of PKC and Calcium pathways. While no deficiencies in expression of TCR complex proteins were seen, we did note defects in early TCR-induced Lck and Zap70 activation, and reduced expression of IKKβ and IKKγ in p50-/-cRel-/- T cells. Beyond established roles in NF-κB activation, we show that IKKβ /γ are also crucial for TCR-induced Lck, Zap70 and PLCγ activation. These findings define a novel pathway of “retrograde signaling” in T cells whereby NF-κB subunits modulate expression of proteins which are crucial for early TCR-induced signaling. Therefore, robust T cell activation occurs in cells exhibiting baseline activation of the pro-survival NF-κB pathway either through TCR tickling or non-TCR pathways.