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 (T_regs) (Gobert and Lafaille 2012, Munoz-Suano, Hamilton and Betz 2011, Rowe, et al. 2013).

Regulatory T Cell involvement with Maternal Fetal Tolerence

Pregnancy is an emotional time for mothers. The constant mood swings, cravings, and nesting syndrome makes the 9 months seem like a lifetime. While the mother is busy attending doctor’s appointments, setting up a nursery and attempting to be ready for a child, her body’s immune system is attempting to reconcile with the fetus growing inside the womb. The immune system sees this new life as a foreign invader attempting to overwhelm the body’s systems (which it kind of is). This is a sign that the immune system should attack and rid the body of the invader. However, if the immune system did this every time a woman got pregnant; our lineage would have ended with Eve. So we as humans have evolved ways to regulate the immune system during pregnancy in order to give birth to health babies. Different stages in pregnancy bring changes in cytokine production (the immune system’s messenger, of which there are many different kinds) to modulate the inflammatory response as needed (1). These changes in cytokine production then produce changes in the cells of the immune system, macrophages (collect debris), natural killer cells (does just what it sounds like it does, kills foreign cells), and regulatory T cells (regulates the other cells in the immune system) (2). Even though these regulatory actions exist there still exists evidence that the maternal immune system can and does respond to fetal antigen (fetal cells).

The presence of maternal antibody (the immune system’s detector) to major histocompatibility complex (MHC) (the complex that presents foreign material) suggests that CD4 T cells can participate in anti-fetal responses (2). A study on the modification of immune cells during pregnancy done by Elizabeth Bonney, examined spleen CD4 T cells of both normal mice and a unique CD4 T cell receptor transgenic mouse specific for the male antigen H-Y (a genetically mutated mouse that cause rejection of fetal material when mated with another H-Y mouse)(3). They found that during pregnancy, these transgenic CD4 T cells become activated and multiply in response to specific antigen and modulate the expression of the CD4 co-receptor (receptor that helps CD4 bind). This data suggest that during pregnancy this particular T cell pool is dynamic and further suggests that there is a specific mechanism of regulation that helps to maintain the coexistence between fetal tolerance and maternal T cell responsiveness.