Malnutrition remains the primary cause of immunosuppression worldwide. Despite profoundly impaired adaptive immunity associated with malnutrition, most humans can survive for extended periods of severe dietary restriction. How the immune system adapts to malnutrition to sustain immunity at barrier surfaces, such as the intestine, remains unknown. Vitamin A deficiency affects an estimated 250 million children in developing countries in the same regions where chronic parasitic worm infections are prevalent. How the immune system integrates dietary cues, like a vitamin deficiency, into the timing of immune responses is still not clear.

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Yasmine Belkaid's team at the National Institute of Allergy and Infectious Disease (Bethesda, MD) posited that compensatory mechanisms might be in place to sustain defined branches of the immunity and, in particular, responses associated with the protection of barrier tissues. They fed pregnant mice a special vitamin A–deficient diet and then kept their offspring on the same regimen to generate vitamin A–deficient mice. They examined the effects of vitamin A deficiency on the intestinal populations of two types of mouse innate immune cells, ILC2 and ILC3, which play major roles in maintaining barrier immunity. While both ICL3 cells and their associated cytokines were significantly reduced in the vitamin A–deficient mice, the levels of ICL2 cells and their associated cytokines went up (Science 343, 432–437; 2014).

Vitamin A supports adaptive immunity through its metabolite, retinoic acid. When retinoic acid was blocked, ILC3 cell populations diminished but ICL2 populations swelled. Introducing undifferentiated progenitor lymphoid cells into mice lacking innate lymphoid cells showed that mice injected with retinoic acid developed a population of cells dominated by ICL3, whereas mice injected with a retinoic acid signaling inhibitor developed a population dominated by ICL2 cells.

Both ILC2 and ICL3 cells are involved in innate immunity, but the former are known to help defend against infectious worms, whereas the latter are known to help defend against bacterial infections. Vitamin A–deficient mice and retinoic acid–inhibited mice did poorly compared with normal mice when challenged with the bacterium Citrobacter rodentium but showed lower loads of Trichuris muris worms than normal mice after being experimentally infected with their eggs.

The findings suggest that vitamin A deficiency can adaptively activate the immune system to help protect mice against worm infections. Belkaid said, “To our knowledge, this is the first study to show a beneficial adaptation of the immune system to nutritional deficiencies.”