Progesterone Modulation of Pregnancy-Related Immune Responses

Abstract

Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy.

Using the Immune System to Manage Immunologically-Mediated Pregnancy Loss

“…Considering that pro-inflammatory cytokines are associated with recurrent pregnancy loss on the one hand [17][18][19][20][21][22][23][24][25] and that progesterone has interesting immunomodulatory capabilities, [35][36][37][38] it stands to reason that progestogens can be considered for downregulating Th1/pro-inflammatory cytokine reactivity.…”

Pregnancy-related immune suppression leads to altered influenza vaccine recall responses

“…We have previously shown that CD4 and CD8 T cell activation, proportions of effector memory T cells expression CD28, Th17 and Treg proportions and some DC and NK cell subsets, all vary during the course of pregnancy (19). Therefore, Data is presented as mean ± standard error of the mean (SEM) or median ± interquartile range (IQR) as appropriate for the distribution normality.…”

“…In the context of influenza A, these DC confer resistance to infection and show improved anti-viral type I IFN production (64). We have previously shown that proportions of mDC and CD83 + mDC do not significantly change during pregnancy (19,65). Therefore, our findings may reflect pregnancy- (30,69,70).…”

“…PIBF is produced following leukocyte interaction with progesterone, which in turn is an important neuroendocrine immune modulator in pregnancy (74)(75)(76)(77). In fact, progesterone has been shown to be a key immunemodulator for anti-viral and cytolytic immune responses in pregnancy (19). However, J o u r n a l P r e -p r o o f as we have previously shown, PIBF expression on NK and -TCR + T cells does not vary a great deal across subsets with gestation in normal healthy pregnancy (19).…”

“…In fact, progesterone has been shown to be a key immunemodulator for anti-viral and cytolytic immune responses in pregnancy (19). However, J o u r n a l P r e -p r o o f as we have previously shown, PIBF expression on NK and -TCR + T cells does not vary a great deal across subsets with gestation in normal healthy pregnancy (19). In non-pregnant mice, progestogen treatment protects against poor outcome during primary H1N1 infection despite reduced anti-viral antibody production and CD8 memory T cell responses (78).…”