Anergic CD8+ T lymphocytes have impaired NF-κB activation with defects in p65 phosphorylation and acetylation.
Because of the cytotoxic potential of CD8(+) T cells, maintenance of CD8(+) peripheral tolerance is extremely important. A major peripheral tolerance mechanism is the induction of anergy, a refractory state in which proliferation and IL-2 production are inhibited. We used a TCR transgenic mouse model to investigate the signaling defects in CD8(+) T cells rendered anergic in vivo. In addition to a previously reported alteration in calcium/NFAT signaling, we also found a defect in NF-κB-mediated gene transcription. This was not due to blockade of early NF-κB activation events, including IκB degradation and NF-κB nuclear translocation, as these occurred normally in tolerant T cells. However, we discovered that anergic cells failed to phosphorylate the NF-κB p65 subunit at Ser(311) and also failed to acetylate p65 at Lys(310). Both of these modifications have been implicated as critical for NF-κB transactivation capacity, and thus, our results suggest that defects in key phosphorylation and acetylation events are important for the inhibition of NF-κB activity (and subsequent T cell function) in anergic CD8(+) T cells.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Paúl E
PE
Clavijo
Kenneth A
KA
Frauwirth
D000107:Acetylation; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061166:Peripheral Tolerance / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation
D016328:NF-kappa B; D051996:Transcription Factor RelA