Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy.
In early human pregnancy, uterine decidual NK cells (dNK) are abundant and considered as cytokine producers but poorly cytotoxic despite their cytolytic granule content, suggesting a negative control of this latter effector function. To investigate the basis of this control, we examined the relative contribution to the cytotoxic function of different activating receptors expressed by dNK. Using a multicolor flow cytometry analysis, we found that freshly isolated dNK exhibit a unique repertoire of activating and inhibitory receptors, identical among all the donors tested. We then demonstrated that in fresh dNK, mAb-specific engagement of NKp46-, and to a lesser extent NKG2C-, but not NKp30-activating receptors induced intracellular calcium mobilization, perforin polarization, granule exocytosis and efficient target cell lysis. NKp46-mediated cytotoxicity is coactivated by CD2 but dramatically blocked by NKG2A coengagement, indicating that the dNK cytotoxic potential could be tightly controlled in vivo. We finally found that in dNK, mAb-specific engagement of NKp30, but not NKp46, triggered the production of IFN-gamma, TNF-alpha, MIP-1alpha, MIP-1beta, and GM-CSF proinflammatory molecules. These data demonstrate a differential, controlled role of NKp46- and NKp30-activating receptors expressed by dNK that could be critical for the outcome of pregnancy and the killing of uterine cells infected by pathogens.
El Costa
Hicham
H
Institut National de la Santé et de la Recherche Médicale; U563. France.
Casemayou
Audrey
A
Aguerre-Girr
Maryse
M
Rabot
Magali
M
Berrebi
Alain
A
Parant
Olivier
O
Clouet-Delannoy
Muriel
M
Lombardelli
Letizia
L
Jabrane-Ferrat
Nabila
N
Rukavina
Daniel
D
Bensussan
Armand
A
Piccinni
Marie-Pierre
MP
Le Bouteiller
Philippe
P
Tabiasco
Julie
J
D018801:CD2 Antigens; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011247:Pregnancy / Q000276:immunology*; D011971:Receptors, Immunologic / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D014599:Uterus / Q000276:immunology*
D018801:CD2 Antigens; D016207:Cytokines; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell