title: 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 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-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.
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA.
authors.forename: Crystina C
authors.initials: CC
authors.lastname: Bronk
authors.forename: Sean
authors.initials: S
authors.lastname: Yoder
authors.forename: Emily L
authors.initials: EL
authors.lastname: Hopewell
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology*; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D052002:NF-kappa B p50 Subunit; D050778:NFATC Transcription Factors; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; C073701:Nfkb1 protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D051966:Phospholipase C gamma
keywords: Gene expression; NF-κB; Signal transduction; T-cell activation; Transcription factors