While during the first trimester of pregnancy natural killer (NK) cells represent the most abundant lymphocyte population in the decidua, their actual function at this site is still debated. In this study we analyzed NK cells isolated from decidual tissue for their surface phenotype and functional capability. We show that decidual NK (dNK) cells express normal surface levels of certain activating receptors, including NKp46, NKG2D, and 2B4, as well as of killer cell immunoglobulinlike receptors (KIRs) and CD94/NKG2A inhibitory receptor. In addition, they are characterized by high levels of cytoplasmic granules despite their CD56 bright CD16 ؊ surface phenotype. Moreover, we provide evidence that in dNK cells, activating NK receptors display normal triggering capability whereas 2B4 functions as an inhibitory receptor. Thus, cross-linking of 2B4 resulted in inhibition of both cytolytic activity and interferon-␥ (IFN-␥) production. Clonal analysis revealed that, in the majority of dNK cell clones, the 2B4 inhibitory function is related to the defi-
IntroductionNatural killer (NK) cells represent a lymphocyte population capable of recognizing and lysing not only tumor cells but also virus-infected cells in the absence of previous sensitization. 1,2 NK-cell function is regulated by a balance between activating and inhibitory signals. 3 Among peripheral-blood NK (pNK) cells, 2 subsets can be identified on the basis of CD56 surface expression: those with low/intermediate levels of CD56 (CD56 dim ) and those with high levels of CD56 (CD56 bright ). 4 CD56 dim NK cells represent the majority (Ͼ 90%) of pNK cells, contain abundant cytoplasmic granules, are highly cytotoxic, and mediate antibody-dependent cell cytotoxicity (ADCC) against IgG-coated target cells through the engagement of CD16. 5 The phenotypically and functionally distinct CD56 bright subset, representing less than 10% of pNK cells, does not express CD16 molecules or expresses low-density CD16 molecules, does not contain cytoplasmic granules, and is poorly cytolytic but has greater cytokine-production capacity. 4 In addition, the 2 pNK-cell subsets differ in their expression of killer-cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A receptor. Thus, CD56 bright pNK cells have low to absent expression of KIRs, whereas they express high levels of CD94/NKG2A inhibitory receptor. In contrast, most CD56 dim pNK cells are KIR positive and express low levels of CD94/NKG2A. 4 During the first trimester of pregnancy, NK cells constitute 50% to 90% of the lymphocytes present in the decidua, a tissue in which B and T lymphocytes are infrequent. It is currently believed that in the early stages of gestation, decidual NK (dNK) cells may play an important role in the control of trophoblastic growth, differentiation, and invasion. Decidual NK cells are phenotypically similar to the CD56 bright pNK cell subset. However, transcriptional geneexpression profiling has shown that dNK cells express both perforin and granzymes at a similar or even higher level than CD56 di...