The Journal of Experimental Medicine
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Published online 21 May 2001.
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© The Rockefeller University Press, 0022-1007/2001/5/1199/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 10, May 21, 2001 1199-1212

Original Article

Human Placental Cytotrophoblasts Attract Monocytes and CD56bright Natural Killer Cells via the Actions of Monocyte Inflammatory Protein 1{alpha}

Penelope M. Drakea,e, Michael D. Gunnk, Israel F. Charog,h,i,j, Chia-Lin Tsoug, Yan Zhouf, Ling Huangf, and Susan J. Fisherb,c,d,f
a Department of Biochemistry and Biophysics, Gynecology, and Reproductive Sciences
b Department of Anatomy, Gynecology, and Reproductive Sciences
c Department of Obstetrics, Gynecology, and Reproductive Sciences
d Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143
e Program in Biological Sciences, University of California at San Francisco, San Francisco, California 94143
f Department of Stomatology, University of California at San Francisco, San Francisco, California 94143
g Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, California 94143
h Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94143
i Daiichi Research Center, University of California at San Francisco, San Francisco, California 94143
j Department of Medicine, University of California at San Francisco, San Francisco, California 94143
k Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina 27710

Correspondence to: Susan J. Fisher, HSW 604, University of California at San Francisco, San Francisco, CA 94143-0512. Tel:415-476-5297 Fax:415-502-7338 E-mail:sfisher{at}cgl.ucsf.edu.

During human pregnancy, the specialized epithelial cells of the placenta (cytotrophoblasts) come into direct contact with immune cells in several locations. In the fetal compartment of the placenta, cytotrophoblast stem cells lie adjacent to macrophages (Hofbauer cells) that reside within the chorionic villus stroma. At sites of placental attachment to the mother, invasive cytotrophoblasts encounter specialized maternal natural killer (NK) cells (CD56bright), macrophages, and T cells that accumulate within the uterine wall during pregnancy. Here we tested the hypothesis that fetal cytotrophoblasts can direct the migration of these maternal immune cells. First, we assayed the chemotactic activity of cytotrophoblast conditioned medium samples, using human peripheral blood mononuclear cells as targets. The placental samples preferentially attracted NK cells (both CD56dim and CD56bright), monocytes, and T cells, suggesting that our hypothesis was correct. A screen to identify chemokine activity through the induction of a Ca2+ flux in cells transfected with individual chemokine receptors suggested that cytotrophoblasts secreted monocyte inflammatory protein (MIP)-1{alpha}. This was confirmed by localizing the corresponding mRNA and protein, both in vitro and in vivo. MIP-1{alpha} protein in conditioned medium was further characterized by immunoblotting and enzyme-linked immunosorbent assay. Immunodepletion of MIP-1{alpha} from cytotrophoblast conditioned medium showed that this chemokine was responsible for a significant portion of the induced monocyte and CD56bright NK cell chemotax-is. These data suggest the specific conclusion that cytotrophoblasts can attract monocytes and CD56bright NK cells by producing MIP-1{alpha} and the more general hypothesis that these cells may organize and act on leukocytes at the maternal–fetal interface.

Key Words: chemokine, pregnancy, leukocyte, immune tolerance, trophoblast


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