Steps Toward Engineering the Immune System: Understanding Lymphoid Cell Regulation in the Intestine

Bostick, John

doi:https://doi.org/10.21985/n2-br00-ej80

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Steps Toward Engineering the Immune System: Understanding Lymphoid Cell Regulation in the Intestine

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Intestinal immunity is a critical contributor to host health. The immune system in the intestine maintains both defense against pathogens and homeostasis of intestinal tissue, which is exposed to environmental influences, including microbes and ingested foods. Proper regulation of the immune response is required to prevent damage to the host. We examined the regulation of the immune system in the intestine by interrogating host and microbial factors. We identified a pair of Helicobacter species that had a negative influence on the proliferation of a subset of innate lymphoid cells (ILCs) that are important for the defense against bacteria. This opens the door for future investigations that explore the molecular factors produced by microbes that may influence the maintenance of ILCs in the intestine. In addition to microbial factors that influence regulation, host factors, like the aryl hydrocarbon receptor (Ahr), a transcription factor that regulates gene expression in response to environmental signals, play an important role. Therefore, we investigated the role of Ahr in regulatory T cells (Tregs), a T cell subset that prevents exuberant immune responses. We found that Ahr regulates the expression of key homing and retention molecules on Tregs, which reduced Treg frequencies in the large intestine and increased frequencies in the circulation and liver. This dysregulation of Treg homing resulted in greater harm to the host under models of intestinal inflammation. We also identified the role of Ahr in Group 2 innate lymphoid cells (ILC2s), which protect the host against tissue damaging pathogens (e.g., allergens and helminths) and help in tissue repair. We discovered that Ahr plays a role in negatively regulating the immune response of ILC2s by regulating the expression of key functional genes. Together, our studies identified key regulatory mechanisms that can be used to engineer new therapies that promote balance in the immune system and can potentially treat or prevent disease.

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