Pergamon PII: SO161-5890(97)00032-l A4olwulur Immunologic, Vol. 34. No. 5. pp. 4 19430. 1997 8~‘ 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0161-5890’97 $17.00+0.00 HUMAN UTERINE NK CELLS HAVE A SIMILAR REPERTOIRE OF KILLER INHIBITORY AND ACTIVATORY RECEPTORS TO THOSE FOUND IN BLOOD, AS DEMONSTRATED BY RT-PCR AND SEQUENCING SUSAN E. HIBY, ASHLEY KING,* ANDREW M. SHARKEY and YUNG WA1 LOKE Research Group in Human Reproductive Immunobiology, Department of Pathology, University of Cambridge, Tennis Court Road. Cambridge CB2 IQP, U.K. (First rrcriwd 16 January 1997; accepted in rc~~~iseri form 6 March 1997) Abstract--The expression of natural killer (NK) cell receptors specific for HLA class 1 molecules has been studied in CD56h”‘h’, CD3- NK cell s isolated from the pregnant uterine mucosa, the decidua. RT-PCR was performed on cDNA from uterine NK cells with primers designed to amplify members of the killer inhibitory receptor (KIR)/killer activatory receptor (KAR) gene family. Sequencing of the PCR products revealed that uterine NK cells express KIR/KAR which have two or three extracellular immunoglobulin superfamily (Ig-SF) domains. NK receptors for both groups of HLA- C alleles were found. KIR, characterised by a long cytoplasmic tail containing the immune receptor tyrosine-based inhibitory motif (ITIM), and KAR, characterised by a short cytoplasmic domain with a transmembrane region containing a charged lysine, were both identified. Different individuals appear to have a distinct but overlapping repertoire of KIR/KAR. No new members of this NK receptor gene family were identified in the uterine CD56b” ‘h’ NK cells. Similar findings were obtained from non-pregnant endometrial tissues representative of different stages of the menstrual cycle. Immunohistology confirmed that the KIR protein products were expressed by decidual NK cells. These results reveal that NK receptors for trophoblast HLA class I molecules are present in maternal uterine NK cells. Fetal trophoblast cells infiltrating the decidua express HLA-G and HLA-C gene products. This suggests that maternal recognition of the fetus may be mediated by an NK allo- recognition system. .(“ 1997 Elsevier Science Ltd Kc,), worrls: NK cells, decidua, KIR, HLA class I INTRODUCTION Large numbers of CD56h”“h’ CD16- cells are found in the uterine mucosa at the time of implantation and during early pregnancy (Starkey et cd., 1988; Nishikawa et al., 1991; King et al., 1989~. 1991). These uterine natural killer (NK) cells have large granular lymphocyte mor- phology, and exhibit moderate cytotoxicity against the NK-sensitive cell line, K562 (Ferry zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA et al., 1990; King et al., 1989h). The relationship of these tissue NK cells to the circulating CD56d’m CD1 6bnLrht cells in peripheral blood is unclear. The functions of uterine NK cells are not known, but as their presence is restricted to the uterine mucosa during placentation there is speculation that they may regulate placental trophoblast migration (King and Loke, 1991; Loke and King, 1995). In humans tro- phoblast cells invade deeply into the uterine mucosa, the decidua. These trophoblast cells express two class I molecules, HLA-G and HLA-C but not HLA-A or HLA- B (Kovats rt nl., 1990; Ellis et al.. 1989, 1990; McMaster *Author to whom correspondence should be addressed. et al., 1995; King et al., 1996). Control of placentation could be exerted by maternal NK cells recog- nising the fetal trophoblast using these HLA class I mol- ecules and other ligands. NK cells can recognise class I molecules resulting in an inhibitory or stimulatory signal (Gumperz and Parham, 1995; Lanier and Phillips, 1996). The NK cell receptors for class I molecules are known as killer cell inhibitory or activatory receptors (KIR/KAR) (Wagtmann et ul., 19950; Colonna and Samaridis, 1995; D’Andrea et ul., 1995; Diihring et al., 1996~). A family of at least 12 related KIR/KAR cDNAs together with probable alleles and splice variants has been described to date. This gene family has been assigned to human chromosome 19 (Wagtmann et al., 1995a). KIR/KAR are all trans- membrane glycoproteins with considerable diversity in the extracellular domain, and have two distinct trans- membrane and cytoplasmic domain arrangements that reflect their inhibitory or activatory signalling roles. The diversity in the extracellular domain allows dis- crimination of different polymorphic class I molecules by these receptors. KIRs/KARs which recognise two dis- tinct subgroups of HLA-C alleles have two immuno-