NF-?B 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-?B, NFAT, and AP-1 to drive clonal expansion of T cells in response to Ag. Genome-wide transcriptional profiling following Ag-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-?B p50 and cRel subunits. Importantly, p50(-/-) cRel(-/-) CD8(+) T cells had significantly diminished NFAT and AP-1 activation compared with WT or PKC?(-/-) CD8(+) T cells. Attenuated NFAT activation after TCR engagement was associated with reduced calcium influx, PLC? and Zap70 activation. Interestingly, pharmacological bypass of PLC?-regulated pathways largely rescued p50(-/-) cRel(-/-) T-cell proliferative defects. These results indicate a crucial and unexpected requirement for NF-?B 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-?B pathway components may be due to impaired proximal T-cell signaling.

SUBMITTER: Bronk CC 

PROVIDER: S-EPMC4261047 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature