Tuesday, November 12, 2013

Maternal Regulatory T Cells: One of Mother’s (and Baby’s) First Lines of Defense

Maternal regulatory T cells play a vital role in maintaining maternal-fetal tolerance and sustaining pregnancies.  By better understanding the mechanisms by which maternal regulatory T cells mediate immune reactions during pregnancy and how pathogens manipulate such immune reactions, it is possible to develop preventative measures against opportunistic pathogens that target mothers during this critical period of time.
In many ways, the immune system’s response to pregnancy is akin to that of organ transplantation; the maternal immune system must determine if the growing fetus poses a threat to the mother’s own survival and if it must be rejected (Gobert and Lafaille 2012). This problem results from the fetus being semiallogenic in nature, meaning that it expresses a combination of both maternal and paternal antigens (Gobert and Lafaille 2012). However, despite the fact that the paternal antigens are considered foreign by the maternal immune system, most maternal immune systems do not cause significant damage to the developing fetus.  This is made possible by the establishment of maternal-fetal tolerance, which increases the probability that the mother’s body will instead perceive the baby as “temporary self” (Trowsdale and Betz 2006).  However, establishing a maternal-fetal tolerance puts the mother at risk by limiting the capacity of her immune system to identify other foreign pathogens that could cause her harm.  Therefore, many non-overlapping mechanisms have evolved to maintain a delicate balance between immunosuppression – to protect the fetus from the maternal immune systems – and immune reactivity – to protect both mother and child from invading pathogens (Munoz-Suano, Hamilton and Betz 2011).   Recent research into maternal-fetal tolerance seeks to shed some light on these mechanisms, particularly those mediated by a subpopulation of T cells called regulatory T cells (Tregs) (Gobert and Lafaille 2012, Munoz-Suano, Hamilton and Betz 2011, Rowe, et al. 2013).

A recent article published in Reproduction Review, entitled “RegulatoryT Cells and the Immune Pathogenesis of Prenatal Infection”, outlined some of the novel roles that maternal regulatory T cells (Tregs) play in sustaining fetal tolerance.  Normally, Tregs are responsible for inhibiting the proliferation of self-reactive T cells via secretion of immunosuppressive cytokines (Abbas and Parjis 1998).  Simply put, their primary job is to ensure that any T cells that could potentially target and mount and immune response against one’s own tissues are eliminated from the T cell repertoire, thus establishing immune system self tolerance.  Maternal Tregs similarly secrete immunosuppressive cytokines, limiting the maternal immune system’s capacity to attack any foreign bodies and thereby providing protection to the developing fetus from the maternal immune system.  
Tregs are unique from the average CD4+ T cell in that they are characterized by the expression of forkhead box P3 protein (Foxp3). Foxp3 is a transcription factor essential for the production and normal function of Tregs (Hori, Nomura and Sakaguchi 2003). Recent studies have found that defects in Foxp3 can result in fatal systemic and organ-specific autoimmunity, further outlining this protein’s importance in maintaining immune tolerance (Rowe, et al. 2013).  To tie this into maternal immunity, Foxp3 expression is found to be induced by trophoblast cells (specialized placental cells) and high-level progesterone (a female hormone that supports gestation and rapidly increases in production throughout pregnancy) (Rowe, et al. 2013). Therefore, we would see expect to, and most often do, see a similarly rapid increase in the prevalence of maternal Tregs after conception.  Additionally, maternal Treg suppression has been experimentally linked to several clinical pregnancy complications, including preeclampsia and spontaneous abortion (Rowe, et al. 2013).  Taking this into account­­, we would expect that these cells must play an important role in maintaining maternal-fetal tolerance.    

However, a balance must be struck between immunosuppression by Tregs and immune reactivity by other immune cells to promote a healthy pregnancy.  The previously mentioned article in Reproduction Review suggests that although maternal Tregs   impair maternal defense against pathogens that exploit the overwhelmed maternal immune system (like listeriosis causing bacteria Listeria monocytogenes), the evolutionary benefits of creating the maternal-fetal tolerance often outweighs such limitations (Rowe, et al. 2013).  Other researchers suggest that the immune system of the mother should not be thought of as suppressed, but rather modulated and streamlined to focus on pathogen recognition, communication, trafficking and repair (Mor and Cardenas 2010).  This suggests that the mother’s immune system is still able to mount an attack, but only when absolutely necessary.  Such modulated mechanisms allow the mother to maintain a well-balanced immune system.   
Overall, what such studies suggest is that we must better understand pathogens that are capable of manipulating the maternal immune system.  By gaining a more concrete understanding of how such pathogens establish infection and how different pathogens causing prenatal infections compare to one another, we can better develop therapeutic strategies that mediate how the immune system targets such pathogens.  By doing so, we will help sustain pregnancies and dramatically improve overall health of both mother and child.

Helpful Links:
For an overview on immune system changes that occur during pregnancy, see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025805/

For general information about regulatory T Cells, see: http://www.ebioscience.com/knowledge-center/cell-type/t-regulatory-cells.htm

For more information on Foxp3, see: http://ghr.nlm.nih.gov/gene/FOXP3

For general information about cytokines and their functions, see: http://pathmicro.med.sc.edu/mobile/m.immuno-13.htm

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