The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/259/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 259-270

Original Article

Interferon {gamma} Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy

Ali A. Ashkara, James P. Di Santob, and B. Anne Croya
a Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1
b Department d' Immunologie, Institut Pasteur, 75724 Paris, France

Correspondence to: Ali A. Ashkar, Dept. of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1. Tel:519-824-8800 ext. 4956 Fax:519-767-1450 E-mail:aashkar{at}uoguelph.ca.

The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-{gamma}. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2-/- common cytokine receptor chain {gamma} [{gamma}c]-/-) or IFN-{gamma} signaling (IFN-{gamma}-/- or IFN-{gamma}R{alpha}-/-) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell–derived IFN-{gamma} during pregnancy, RAG-2-/-{gamma}c-/- females were engrafted with bone marrow from IFN-{gamma}-/- mice, IFN-{gamma} signal-disrupted mice (IFN-{gamma}R{alpha}-/- or signal transducer and activator of transcription [Stat]-1-/-), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-{gamma}-/- mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-{gamma}R{alpha}-/- or Stat-1-/- mice overproduced uNK cells, all of which were immature. Grafts from IFN-{gamma}-/-, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-{gamma} to pregnant RAG-2-/-{gamma}c-/- mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell–derived IFN-{gamma} modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.

Key Words: interferon {gamma} signaling, uterine lymphocytes, decidual spiral arteries, bone marrow transplantation, tumor necrosis factor {alpha}


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