NF-kappaB-regulated suppression of T-bet in T cells represses Th1 immune responses in pregnancy.

The molecular mechanisms that suppress Th1 immune responses in pregnancy are unknown. We assessed the expression of the Th1 cytokine transcription factor T-bet. We isolated PBMC and T cells from non-pregnant and pregnant women and demonstrated that T-bet is specifically down-regulated in pregnancy under basal and stimulated conditions. Low levels of T-bet protein were detected in the nuclear fraction of unstimulated PBMC from non-pregnant, but not pregnant women. Nuclear levels of T-bet increased in response to PMA/ionomycin in PBMC from non-pregnant, but not pregnant women. T-bet expression was greater in whole cell lysates of stimulated CD3(+) T cells from non-pregnant relative to pregnant women. NF-kappaB is specifically down-regulated in T cells in pregnant women, resulting in suppressed expression of Th1 cytokines IL-2, IFN-gamma and TNF-alpha. In this study, down-regulation of NF-kappaB also resulted in diminished expression of T-bet. PMA induces NF-kappaB translocation, T-bet expression and IL-2, IFN-gamma and TNF-alpha production. Conversely, pre-incubation with SN50, and NF-kappaB oligodeoxyribonucleotide decoys suppressed PMA-induced NF-kappaB translocation and gene transcription, respectively, resulting in diminished T-bet expression and Th1 cytokine production. Therefore, maintenance of the cytokine environment for pregnancy success is mediated via strict regulation of Th1 immune responses, more specifically through control of NF-kappaB and T-bet transcription.