Depletion of CD8+ Cells Abolishes the Pregnancy Protective Effect of Progesterone Substitution with Dydrogesterone in Mice by Altering the Th1/Th2 Cytokine Profile

Abstract

One of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity’s pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8+ cells and cytokine expression (IL-4, IL-12, TNF-α, IFN-γ) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution.

Cortisol levels and very early pregnancy loss in humans

“…(51). Additionally, immune challenges in mice appear to promote a shift in the Th1͞Th2 cytokine ratio, which has been associated with low progesterone levels and early spontaneous abortion (24,52). Another possible mechanism is suggested by cell-culture studies in rabbits showing that glucocorticoids can cause degeneration and premature aging of the trophoblast (53,54).…”

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

“…61 In the present study, we did not investigate levels of TNF-␣, however, using the sonic stress-exposure model, which we use in various experimental settings, revealed an increase of TNF-␣-positive cells on stress exposure in the uterus. 62 In the context of alternate death pathways, it is also noteworthy that experiments in mice with disrupted genes for Fas or Fas ligand suggest an important pathogenetic role for apoptosis induced through the Fas/Fas ligand system in hair follicle melanocyte apoptosis in chemotherapy-induced hair loss and alopecia areata. 63,64 The next question raised by our findings is how this release of NGF triggers or exacerbates deleterious inflammatory events such as mast cell activation or migration of MHC II ϩ antigen-presenting cells, eg, activated macrophages.…”

Adaptive Immune Responses During Pregnancy

“…88 An important aspect is the fact that viral infections can skew the CD8 + cell repertoire and can alter the dynamic of CD8 + cells during pregnancy. A pro-inflammatory profile may augment the influx of T cells into the fetal-maternal interface, and Treg may not be longer able to protect from effector mechanisms and/or activate antigen-specific CD8 + cells to attack fetal structures.…”