The immune system of a fetus developing in the womb faces a quandary: It has to prepare itself to attack dangerous pathogens after birth, by distinguishing its own cells from those of invaders. But until that time, it needs to avoid attacking the mother, whose cells are also “foreign.” A new study of fetal tissue has revealed one way the developing immune system keeps itself in check: by interrupting the production of a key weapon in the body’s arsenal against invaders.
The new insights might help researchers better understand certain types of miscarriages and a deadly immune response in premature babies. It also could lead to new ways to keep the adult immune system in check when it gets out of balance.
To better understand how the different pieces of the immune system develop, immunologists Florent Ginhoux and Naomi McGovern at the Agency for Science, Technology and Research (A*STAR) in Singapore and their colleagues studied tissue from nearly 100 elective abortions performed between 14 and 22 weeks of gestation. Consistent with other studies, they found that as early as 13 weeks of development, the fetus was producing a range of immune system cells, including dendritic cells, which recognize invaders and signal other immune cells to attack. These cells were fully functional, the researchers found: In lab experiments, they responded as well as adult dendritic cells to molecules that mimic pathogens, the researchers report today in Nature.
Dendritic cells usually send out signals that ramp up proliferation of another type of immune cell, T cells, which then attack invaders. But when the researchers added the dendritic cells to a mix of adult immune cells, the fetal dendritic cells triggered more than the usual number of T regulatory cells, which keep the production of T cells in check. The researchers also found that different genes were switched on in fetal dendritic cells than in adult dendritic cells. In particular, fetal cells made high amounts of arginase-2, an enzyme that breaks down L-arginine, a key ingredient in the production of a key messenger named tumor necrosis factor alpha (TNF-alpha). TNF-alpha triggers inflammation, a general state of war against an invader; make less of it, and your immune system reacts less aggressively. “The system is fully active and able to respond,” Ginhoux says, but at the same time it has built-in brakes.
The insight “builds nicely on a number of studies” showing that parts of the fetal immune system are in place fairly early in development, says Jakob Michaelsson, an immunologist at the Karolinska Institute in Stockholm. The fetal cells’ ability to keep the immune response in check is quite potent, he says, and harnessing that ability in adults could lead to new ways to treat autoimmune diseases, in which the body improperly attacks its own cells. In another set of experiments, the researchers found that fetal dendritic cells could block the production of TNF-alpha by adult T cells as well.
Ginhoux and his colleagues also note that high levels of TNF-alpha are common in some types of miscarriage, gestational diabetes, and necrotizing enterocolitis, an out-of-control immune reaction that often afflicts premature infants. The arginase-2 pathway might be a way to better understand and perhaps find treatments for those conditions, Ginhoux says.