NF‐κB is crucial in proximal T‐cell signaling for calcium influx and NFAT activation

Abstract

In the accepted model of T-cell activation, parallel signal transduction pathways activate the transcription factors NF-κB, NFAT and AP-1 to drive clonal expansion of T cells in response to antigen. Genome-wide transcriptional profiling following antigen-induced CD8+ T-cell activation in C57BL/6 mouse T cells revealed that genes regulated by NFAT were also reduced in the absence of NF-κB p50 and cRel subunits. Importantly, p50−/−cRel−/− CD8+ T cells had significantly diminished NFAT and AP-1 activation compared with WT or PKCθ−/− CD8+ T cells. Attenuated NFAT activation after TCR engagement was associated with reduced calcium influx, PLCγ and Zap70 activation. Interestingly, pharmacological bypass of PLCγ regulated pathways largely rescued p50−/−cRel−/− T-cell proliferative defects. These results indicate a crucial and unexpected requirement for NF-κB p50 and cRel subunits in proximal TCR signaling and calcium responses. They further suggest that key defects in T cells in the absence of NF-κB pathway components may be due to impaired proximal T-cell signaling.

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