Mother's Body Teaches Fetal Immune System Not to Attack Itself Before Birth

Even before we are born, our immune system is hard at work. New research shows how the developing fetal immune system takes advantage of the time and opportunity of gestation — in the presence of mom's cells and tissues — to develop a sense of self.

Contrary to widely held belief, a developing fetus does have an active and functional immune system, and it develops much earlier than previously thought, according to lead authors Jerry Kok Yen Chan and Florent Ginhoux, from Singapore Immunology Network in Singapore. They present their findings in a new study,published June 14 in Nature.

Fighting the Foreign

When something foreign, like an invading bacteria, is detected in our body, dendritic cells capture and digest it. The dendritic cells attach the digested bits of foreign material (called antigens) to MHC proteins. The MHC protein and foreign antigen complex migrates to the surface of the cell, holds up the antigens as a foreign invader, and waits for a T lymphocyte to come along. That T lymphocyte sees the antigen-MHC complex and is "turned on" to seek out and kill any other invaders bearing the same antigens. Some antigen-presenting cells travel to lymph nodes where many T cells reside and spread the word to the rest of the body.

Macrophages (larger cells with projections) interacting with T lymphocytes

The ability to know what is a microbial invader and what's a normal part of our complex bodies depends on this process of teaching the body what antigens are foreign and which belong to the body. If the body fails at training itself at recognizing foreign invaders, it won't be able to fight off infections. But if it fails at teaching itself to ignore "self" proteins, autoimmune diseases can result. For example, in Type 1 diabetes, the body attacks and kills pancreas cells because it sees them as foreign.

How antigen processing happens in a fetus hasn't been clear, especially since the developing immune system hasn't learned how to make the distinction between foreign and self.

Chan and Ginhoux have shown that not only does antigen presentation occur during fetal development, its role there is not to present foreign antigens and mount an immune response against them. Instead, the immature immune system uses this time to develop the ability to tell the difference between the "self" proteins that we don't want to raise an immune response to — because they belong to mom or us.

Sense of Self and Tolerance of Mom

We might not think of fetuses as needing to fight off foreign invaders, but in the womb, babies are constantly exposed to antigens from proteins in the mother's cells. Dangers arise if the immune system attacks the mothers' cells, so the fetus needs to learn what's "self," what's "mom," and what's the potentially dangerous "other."

The research team found that fetuses as early as the second trimester have the same kinds of antigen-presenting dendritic cells as adults do. Bearing MHC-antigen complexes on their surface, they migrate to lymph nodes, just like adult antigen-presenting cells.

However, the study team found that the fetal immune system responded differently than an adult's. When presented with an antigen, T cells were not stimulated to kill the source of the antigen. Instead, the presentation activated a subset of immune cells called T regulatory cells. The T regulatory cells inhibited an immune response to the antigen. In this way, the immune system of the developing fetus learned that antigens come from fetal and maternal cells encountered and chewed up by dendritic cells were to be "tolerated," not foreign.

The fetal immune system developed tolerance to maternal antigens it inherited, as well as those it didn't inherit but learned to tolerate through this process. The study authors believe their work may help explain our lifelong tolerance of non-inherited maternal antigens.

Fetal T cells produced less of the cytokine TNF-a — a protein that can signal activation of an immune response — than adult T cells do. Some pregnancy complications, including recurrent spontaneous miscarriage and gestational diabetes, are associated with elevated levels of TNF-a, so future studies related to the new research findings may shed light on those conditions.

In the yin and yang of our immune system, development of our immune response involves figuring out what we do and don't want to see as foreign. The new study by Chan and Ginhoux have just explained when and how we develop an immune tolerance to our cells and those of our mother.