NK Cells Expressing a Progesterone Receptor Are Susceptible to Progesterone-Induced Apoptosis

Abstract

It has been proposed that progesterone (P4) induces the suppression of immune responses, particularly during pregnancy. However, knowledge about the mechanisms involved has remained largely elusive. We demonstrate herein that peripheral blood NK (PBNK) cells express both classical progesterone receptor (PR) isoforms and are specifically affected by the actions of P4 through two apparently independent mechanisms. Progesterone induces caspase-dependent PBNK cell death, which is reversed by two different anti-progestins, ZK 98.299 and RU 486, supporting the involvement of classical PR isoforms. It was suggested that CD56brightCD16− killer Ig-like receptor (KIR)− NK cells might represent precursor cells, which, upon activation, acquire the features of a more mature NK subset expressing KIR receptors. The present study demonstrates that PR expression seems to be restricted to more mature KIR+ PBNK cells. The expression of PR had a functional counterpart in the suppressive effect of P4 on IL-12-induced IFN-γ secretion. This cytokine suppression was mainly observed in KIR+ PBNK cells, without affecting the high secretion of IFN-γ by CD56bright PBNK cells. The lack of PR expression on CD56brightKIR− PBNK cells provides an additional phenotypic marker to test the idea that they might represent the PBNK precursors selectively recruited into the endometrium where they differentiate to become the uterine NK cells. Additionally, these findings may be relevant to NK cell function in viral immunity, human reproduction, and tumor immunity.

Natural killer cell-triggered vascular transformation: maternal care before birth?

“…5,37 The presence of NK cells in the cycling uterus even if the implantation site is outside of the uterus clearly indicates that human uNK cells, like those in rats and mice, are induced by endocrineregulated stromal signals and not by the presence of trophoblast or of a conceptus. During the progesterone-dominant phase of the menstrual cycle, uNK cells associate with elongating spiral arteries [38][39][40] and with basal components of uterine glands. During this interval, human uNK cells may have actions not seen in mice due to the lack of mouse uNK cells prior to conception.…”

Fluctuation of Peripheral Blood T, B, and NK Cells during a Menstrual Cycle of Normal Healthy Women

“…Through the PRs, progesterone induces apoptosis of NK cells and suppresses IL-12-induced IFN-g production of KIR + NK cells. Expression of PRs in T and B cells is insignificant and peripheral blood CD56 bright , and uterine NK cells do not express PRs (11).…”

“…Estrogen exerts immune regulation via estrogen receptors (ERs) on the lymphocytes, and receptors for estrogen, progesterone, androgen, and glucocorticoid are found in lymphoid organs and/or lymphocytes (9,10). Compared with the ERs, nuclear progesterone receptor (PR) expression is restricted in peripheral blood NK cells, especially killer Ig-like receptor (KIR) + cells (11). Through the PRs, progesterone induces apoptosis of NK cells and suppresses IL-12-induced IFN-g production of KIR + NK cells.…”

Children's Immunology, what can we learn from animal studies (1): Decidual cells induce specific immune system of feto-maternal interface

“…Immature uNK cells were positive for VLA--tor) chains. Otherwise, mature uNK cells were positive --ies revealed that uNK cells express the estrogen receptor and is not the relationship between these steroid receptors and success of pregnancy (Arruvito et al, 2008). The experiment of differentiation of murine uNK cells in the ectopically grafted uterine tissues showed that the decidualization of the endometrium is necessary for the differentiation of uNK cells, but the other factors that have direct effect to the uNK cells remain unknown.…”