Gut microbes are known to help the immune system mature, but the exact way they do this has not been clear. Now, a study done in mice shows that the microbiota helps build the gut immune system by a diet-derived signal—vitamin A—to developing immune cells.

The findings, published in Cell Host & Microbe, suggest that gut microbes help shape early gut immunity by controlling access to dietary vitamin A, which helps T cells mature and settle in the gut.

Scientists have known that gut microbes and vitamin A both help specific gut immune cells mature and settle in the intestine. But it’s unclear how gut microbes and dietary vitamin A signals were connected to guide the maturation and gut-targeting of these developing immune cells. 

So, Tarun Srinivasan at the University of Texas Southwestern Medical Center in Dallas and his colleagues traced vitamin A-derived molecules in mice to see how gut microbes influence immune development.

Carrier proteins

In mice with normal gut microbes, vitamin A-derived molecules moved first into the cells lining the gut, then into nearby immune cell precursors, then into specific immune cells called T cells in the lymph nodes, and finally into intestinal T cells. 

When mice were treated with antibiotics, this movement was disrupted, while restoring the microbiota restarted it. The process depended on gut bacteria triggering the gut lining to make carrier proteins called serum amyloid A, which helped deliver vitamin A to immune cell precursors and guide them to lymph nodes.

Antibiotics reduced serum amyloid A production, and mice lacking serum amyloid A had poor vitamin A transfer to immune cell precursors. When the researchers engineered mice to keep making serum amyloid A even without gut microbes, vitamin A transfer to immune cell precursors was restored. 

Regulating immunity

The researchers also found that serum amyloid A proteins help immune cell precursors express a migration signal that guides them to lymph nodes. There, the cells pass the vitamin A signal to developing T cells, but only when the T cells recognize specific microbial signals. 

When serum amyloid A proteins were lacking or vitamin A signaling was disrupted, T cells were less able to mature and acquire the molecular labels that helped them move into the gut. As a result, fewer T cells accumulated in the intestinal tissue, the researchers found. 

“These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal,” the authors say. However, they add, the exact chemical form of the vitamin A signal transferred to T cells and the molecular details of the handoff between immune cells are still unclear.