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Originally published online as doi:10.2353/ajpath.2008.071169 on August 7, 2008

Published online before print August 7, 2008
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(American Journal of Pathology. 2008;173:653-664.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071169

Granulysin Produced by Uterine Natural Killer Cells Induces Apoptosis of Extravillous Trophoblasts in Spontaneous Abortion

Akitoshi Nakashima*, Arihiro Shiozaki*, Subaru Myojo*, Mika Ito*, Mikiko Tatematsu*, Masatoshi Sakai*, Yasushi Takamori{dagger}, Kazuyuki Ogawa{ddagger}, Kinya Nagata{ddagger} and Shigeru Saito*§

From the Department of Obstetrics and Gynecology,* Faculty of Medicine, University of Toyama, Toyama; the StemCell Institute Inc.,{dagger} Tokyo; the R&D Center,{ddagger} BML, Saitama; and the 21st Century COE Program,§ University of Toyama, Toyama, Japan

Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56bright NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56bright NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.






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