Regulated suppression of NF-κB throughout pregnancy maintains a favourable cytokine environment necessary for pregnancy success

Th1 immune responses are suppressed in pregnancy, but the temporal regulation and the mechanism(s) underlying this immune alteration are unknown. We assessed the expression of Th1 cytokines IFNγ, IL-2 and TNFα in response to stimulation in isolated T-cells from pregnant women throughout gestation. Using flow cytometry we demonstrated an early and sustained reduction in IFNγ and IL-2 production in CD3+ T-cells, but TNFα levels are not reduced until the third trimester. We assessed the expression of NF-κB and T-bet, transcription factors that play a central role in Th1 immune responses, throughout pregnancy. In isolated T-cells levels of available p65 were suppressed early in pregnancy, but T-bet expression was suppressed only in the third trimester. In contrast to p65, T-bet expression was transcriptionally regulated, with diminished T-bet mRNA in third-trimester samples. Re-expression of p65 in T-cells from third-trimester pregnant women resulted in an induction of T-bet expression in response to PMA stimulation and a concomitant increase in the production of IL-2 and IFNγ. The suppressive effect of pregnancy was ameliorated as early as 72 h post-partum when p65 levels returned to normal as did the level of inducible IFNγ and IL-2. TNFα levels in post-partum women were significantly increased relative to non-pregnant controls. The pregnancy-specific suppression of p65 and subsequent loss of cytokine production suggest that this transcription factor acts specifically to regulate the cytokine environment that is required for pregnancy success.