Researchers have shown that the offspring of pregnant mice raised on a low-vitamin A diet developed smaller lymph nodes than did animals exposed to higher levels of the nutrient in utero. The vitamin-deprived mice also had fewer Peyer’s patches, lymph node-like structures in the intestine. The same was true for murine embryos genetically engineered to have defective receptors for the vitamin A metabolite retinoic acid. After birth, a normal diet did not reverse the effects of the in-utero deficiency, which seemed to hinder mice in fighting infections even as adults.
“What we found is that there is a tight link between the maternal diet during pregnancy and the immune fitness of the offspring,” said Henrique Veiga-Fernandes, who led the study. “In other words, whatever the mother eats during pregnancy will have an irreversible impact on the later health of the progeny.”
“Vitamin A has been shown to have many effects in the developing fetus. Vitamin A is involved in many developmental processes: it’s involved, of course, in vision, development of the eyes [and] retina, and after birth, it has been shown [to have] effects on the immune system,” said Gérard Eberl, of the Pasteur Institute in Paris, who wrote an editorial accompanying the study but was not involved in the work. “This paper is new because it shows that vitamin A provided by the mother to the fetus has an effect on the development of the immune system, and that is really significant.”
“This is the first demonstration that any dietary maneuver during pregnancy can impact lifelong immune function of the offspring,” wrote David Chaplin, who studies the development of lymphoid organs at the University of Alabama at Birmingham but was not involved in the work, in an e-mail to The Scientist.
Previous research on the development of the secondary lymphoid organs—which, beyond lymph nodes and Peyer’s patches, include the spleen—found that the process was strictly programmed. The present study is the first to suggest that this development can be altered by maternal behavior.
“We always thought that the development of the organs of the immune system was sort of an autonomous process,” said Tom Cupedo, an immunologist at the Erasmus Medical Center in Rotterdam, The Netherlands, who was not involved in the work. “But now I think what this paper shows is that, actually, maternal diet [can] influence how the organs of the immune system, and therefore the functioning of the immune system . . . develop.”
Beyond lymph node size, the researchers sought to examine other ways vitamin A might affect the developing immune system. During immune system development, lymphoid tissue inducer cells with the marker CD4 (LTi4) are important for the formation of lymph nodes and other secondary lymphoid organs. These cells are distinct from another type of innate lymphoid cell, which lacks CD4 (ILC4neg).
The researchers found that retinoic acid influences the differentiation of these inducer cells. They fed pregnant mice a retinoic acid-enriched diet and found that the ratio of LTi4 cells to ILC4neg cells in the embryo increased. An inhibitor of retinoic acid signaling had the opposite effect. Embryos with retinoic acid receptor mutations had a smaller percentage of inducer cells than controls. The researchers therefore proposed that vitamin A is important for the differentiation of these LTi4 cells.
Having established that a normal diet after birth did not reverse the effects of vitamin A deprivation in utero, the researchers wondered whether a bone marrow transplant might achieve this effect. The researchers took the offspring with the retinoic acid receptor mutations and transplanted them with hematopoietic stem cells from wild-type mice. The transplant did not reverse the effects of the vitamin A deficiency. Even with the transplanted stem cells, the offspring that were exposed to low vitamin A in utero had smaller lymph nodes and, as adults, fought a viral lung infection less effectively than controls—wild-type mice transplanted with the same stem cells.
“We always used to think of this as sort of a binary process—either you develop lymph nodes or you don’t,” said Cupedo. “Now this really shows that there are intermediates and that you can have size issues that really affect how the immunity to infection in later life occurs.”
S. van de Pavert et al., “Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity,” Nature, doi:10.1038/nature13158, 2014.