Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells

Abstract

Behavioral abnormalities in offspring of murine dams that receive immune stimulation with (poly)I:C during pregnancy are well-documented. In this prenatal model, (poly)I:C-induced maternal cytokines, particularly IL-6, appear involved in the etiology of the behavioral abnormalities. While much has been published on the abnormal behaviors of offspring in this model, much less is known about how maternal immune stimulation affects the adaptive immune system of the offspring, and its possible role in the observed pathophysiology. In the present study, pregnant dams were stimulated with (poly)I:C at E12, and 24h later cytokine levels were measured in maternal sera and amniotic fluids. Lymphocytes from offspring were also analyzed for T Helper (TH) cell subsets. The results demonstrate that lymphocytes from offspring of pregnant dams stimulated with (poly)I:C develop into TH17 cells upon in vitro activation. This preferential TH17 cell differentiation occurs in offspring of pregnant dams with an immunological "memory" phenotype, but not in offspring of immunologically "naive" dams. Comparable levels of IL-6 were found in the sera of immune and naïve pregnant dams, however, there was a disparity between levels of IL-6 in maternal sera and amniotic fluids of (poly)I:C-injected dams. In matings between IL-6 KO dams (IL-6-/-) and wild-type males (IL-6+/+) there was no IL-6 in sera from (poly)I:C-injected dams, but there were high levels of IL-6 in their amniotic fluids. Analysis of supernatants of cultured placental cell preparations from these IL-6 KO dams confirmed that the IL-6 was produced from the fetal (IL-6+/-) component, and heterozygous IL-6+/- offspring could also produce IL-6.