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Protein Secreted by the Fetus During Pregnancy May Reprogram Immune Cells

Results from an NIAID study suggest that natural killer (NK) cells, immune cells usually dedicated to killing virus-infected cells and tumor cells, acquire new functions to help expand blood vessels in the uterus during pregnancy. This reprogramming of the mother’s NK immune cells occurs in response to a signal sent by the fetus. The study appears online in the November 26th issue of the Proceedings of the National Academy of Sciences of the United States of America.

photo of a pregnant woman
Credit: NIAID


During normal pregnancy, blood vessels in the decidua, the tissues that line the uterus, must remodel to supply enough blood and nutrients to the growing fetus. Without proper vascular remodeling, pregnancy complications can occur, including poor growth of the fetus, high blood pressure in the mother, and, in some cases, spontaneous abortion.

NK immune cells in the bloodstream primarily function to clear tumor cells and microbe-infected cells from the body. But during pregnancy, these cells, which are abundant in the uterus, contribute to placental growth by enhancing the blood supply to the fetus.

Previous work by Sumati Rajagopalan, Ph.D., a staff scientist in the laboratory of Eric Long, Ph.D., chief of the Molecular and Cellular Immunology Section in the NIAID Laboratory of Immunogenetics, showed that a human placental protein produced by cells of the fetus, HLA-G, binds to a specific receptor on NK immune cells called CD158d. The next step was to examine the response that results from this binding.

Results of Study

Drs. Rajagopalan and Long observed that when a protein binds to CD158d, the receptor activates, initiating signals within the NK immune cells that prevent the cells from dividing or dying, a state known as senescence. As part of this senescence response, NK immune cells release a large array of proteins associated with tissue remodeling and blood vessel formation.

The current study provides a possible explanation for what happens when maternal NK immune cells respond to the fetal HLA-G protein. This protein binds to the mother’s NK immune cells and keeps them in a state of senescence. The proteins released as part of the senescence response may influence pregnancy success.

The investigators next looked at changes in gene expression in the treated NK immune cells. Their analysis revealed that genes associated with inflammation, wound healing, and cell senescence increased in expression as a result of CD158d activation. These genes, in turn, make proteins that promote tissue remodeling and blood vessel formation and keep NK cells immune alive long enough to accomplish these tasks. The investigators termed this pattern of gene expression a “senescence signature,” which is similar to an expression pattern that is induced by other triggers of senescence, such as cancer-causing genes or damaged DNA.

To determine if senescent NK immune cells could stimulate blood vessel formation, the investigators added cell culture media taken from NK immune cells after CD158d activation to human endothelial cells, which form the lining of blood vessels. The team observed that endothelial cells migrated to form a network of tubes, characteristic of the beginning formation of blood vessels. These endothelial cells also showed an increase in vascular permeability, the capacity of vessel walls that allows large molecules and cells to flow in and out, a prerequisite for tissue remodeling and new blood vessel formation.


The NIAID team demonstrated that CD158d activation transforms NK immune cells into cells that promote blood vessel formation. Although NK immune cells represent a relatively small percentage of the circulating immune cell population, they are one of the most abundant cell types found in the maternal uterine tissue in early pregnancy.

Because increased numbers of NK immune cells appear in the uterus during early pregnancy and release proteins associated with tissue remodeling and blood vessel formation, understanding how these cells are regulated could provide new insights into pregnancy complications due to poor fetal blood supply.

Next Steps

The NIAID investigators plan to explore in more detail how the fetal protein HLA-G binding to the NK immune cell receptor CD158d triggers changes in NK immune cells. They have produced an antibody that can stimulate CD158d, similar to HLA-G, which can be used to mimic HLA-G activity.

Although this antibody, if made for people, could potentially treat pregnancies with incomplete vascular remodeling, ethical concerns prohibit clinical studies involving pregnant women. Additionally, the only animals that express CD158d and HLA-G are chimpanzees and other great apes, which are difficult to study.

But HLA-G expression also has been found in some cancer cells, suggesting that NK immune cell reprogramming could stimulate the formation of a blood supply to a tumor. The researchers speculate that antibodies or reagents that block HLA-G binding to CD158d or signaling by CD158d could be useful in treating certain cancers that also produce HLA-G.


Rajagopalan S and Long EO. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc. Natl. Acad. Sci. U. S. A. Nov. 26, 2012 (online ahead of print).

Dr. Long’s Lab

Last Updated December 04, 2012