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NK Cells Expressing a Progesterone Receptor Are Susceptible to Progesterone-Induced Apoptosis¹

Lourdes Arruvito^*,, Sebastián Giulianelli, Ana C. Flores^*,, Natalia Paladino^*,, Marcos Barboza^*, Claudia Lanari and Leonardo Fainboim^2,*,

^* Immunogenetics Laboratory, "José de San Martín" Clinical Hospital, Department of Microbiology, Parasitology and Immunology, School of Medicine, University of Buenos Aires, and Laboratory of Hormonal Carcinogénesis, Instituto de Biología y Medicina Experimental, National Council for Scientific and Technological Research, Buenos Aires, Argentina

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 CD56^brightCD16^– 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- secretion. This cytokine suppression was mainly observed in KIR⁺ PBNK cells, without affecting the high secretion of IFN- by CD56^bright PBNK cells. The lack of PR expression on CD56^brightKIR^– 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant PICT 08814 from the Agencia Nacional de Promoción Científica y Tecnológica.

² Address correspondence and reprint requests to Dr. Leonardo Fainboim, División Inmunogenética, Hospital de Clínicas "José de San Martín," Facultad de Medicina, Universidad de Buenos Aires, Avenida Córdoba 2351 (1120), Buenos Aires, Argentina. E-mail address: lfainboim{at}hospitaldeclinicas.uba.ar

³ Abbreviations used in this paper: PBNK, peripheral blood NK; P4, progesterone; PR, progesterone receptor; KIR, killer Ig-like receptor; RT, room temperature; PI, propidium iodide; DEX, dexamethasone; ZK, ZK 98.229; RU, RU 486; PBST, PBS with Tween 20; E2, 17β-estradiol; GR, glucocorticoid receptor; DC, dendritic cell; uNK, uterine NK cells; MPA, medroxiprogesterone acetate.