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Previous studies have demonstrated that T-helper 17 (T H 17) cells and cytolytic natural killer (cNK) cells are increased in women with preeclampsia. In this study we investigated the role of placental ischemia-stimulated T H 17 cells in induction of cNK cells in pregnancy. We further assessed the role of T H 17 cell-mediated oxidative stress in facilitation of cNK cell activation in pregnancy by treating rats with the SOD mimetic tempol. CD4 + /CD25 −  cells were isolated from reduced uterine perfusion pressure (RUPP) rats and differentiated into T H 17 cells in vitro. On day 12 of gestation ( GD12), 1 × 10 6  placental ischemia-stimulated T H 17 cells were injected into normal pregnant (NP) rats (NP + RUPP T H 17 rats), and a subset of rats were treated with tempol (30 mg·kg −1 ·day −1 ) from GD12 to GD19 (NP + RUPP T H 17 + tempol rats). On GD19, cNK cells, mean arterial pressure, fetal weight, and cNK cell-associated cytokines and proteins were measured. Placental cNK cells were 2.9 ± 1, 14.9 ± 4, and 2.8 ± 1.0% gated in NP, NP + RUPP T H 17, and NP + RUPP T H 17 + tempol rats, respectively. Mean arterial pressure increased from 96 ± 5 mmHg in NP rats to 118 ± 2 mmHg in NP + RUPP T H 17 rats and was 102 ± 3 mmHg in NP + RUPP T H 17 + tempol rats. Fetal weight was 2.37 ± 0.04, 1.95 ± 0.14, and 2.3 ± 0.05 g in NP, NP + RUPP T H 17, and NP + RUPP T H 17 + tempol rats, respectively. Placental IFNγ increased from 1.1 ± 0.6 pg/mg in NP rats to 3.9 ± 0.6 pg/mg in NP + RUPP T H 17 rats. Placental perforin increased from 0.18 ± 0.18 pg/mg in NP rats to 2.4 ± 0.6 pg/mg in NP + RUPP T H 17 rats. Placental levels of granzymes A and B followed a similar pattern. Treatment with tempol did not lower placental cNK cytokines or proteins. The results of the present study identify T H 17 cells as a mediator of aberrant NK cell activation that is associated with preeclampsia.

american journal of physiology. regulatory, integrative and comparative physiology/american journal of physiology. regulatory, integrative, and comparative physiology

Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy