Diet – not only nutrition but also essential for education of the immune system

The focus of most nutritional studies is on the effect of dietary components on metabolism and host physiology. The links between nutrition and immunity were first described in clinical studies in malnutrition. Controversies still abound about the impact of nutrition on both intestinal and systemic immune responses and it is not yet fully understood. Studies have however shown that both dietary and microbial antigens are required for the normal development of the mucosal immune system. So far, the immunological interest in diet was mostly linked to pathologic conditions, such as  food intolerance or intestinal inflammation. In contrast, not much is known about the role of dietary antigens in the development and function of the gut associated-lymphoid tissue (GALT).

A manuscript published in the Journal of Clinical Investigation, by Alexander Visekruna et al.  from the Institute for Medical Microbiology and Hygiene at Philipps University in Germany, remarkable experiments were performed that have altered our immunological view of nutrition. Based on their findings, they proposed a new model explaining how the intestinal immune system develops and maintains homeostasis in the presence of dietary antigens.

The research team observed that dietary antigens induce a vital immune response in the Peyer´s patches, which is a prerequisite for functional mucosal immunity and development of the small intestine. Paradoxically, it is this immune response that also provides immune tolerance against nutrition and probably also other antigens. You might wonder why this aspect of diet has not been discovered earlier. One explanation is that other studies dealing with the role of dietary antigens mainly focused on immune cells within the lamina propria and mesenteric lymph nodes even though the lamina propria is not considered a typical immune induction site. These studies however paid little or no attention to Peyer patches, known to effectively stimulate B and T cells.

Here, the authors (Visekruna et al.) showed that in the presence of dietary antigens, CD4⁺ T cells in Peyer´s patches were highly activated. These food-activated Helios⁺Foxp3⁻CD4⁺ T cells lacked molecules required for long-term survival, a typical feature of cells undergoing apoptosis. In addition, PD-1, a known regulator of T cell activation and apoptosis, was found to be selectively expressed on Helios⁺ T cells of the Peyer patches. They could demonstrate that the continuous uptake of dietary antigens increasingly activates Peyer´s patch CD4⁺ T cells until they are overstimulated and commit suicide, called apoptosis. The death of diet activated T cells has a positive effect as macrophages that ingested apoptotic T cells in the Peyer´s patches produced substantial amounts of anti-inflammatory Interleukin-10 compared to animals fed on antigen free elemental diet. They further expanded their studies to patients with Crohn’s disease (CD) and revealed that their Peyer´s patches contained increased numbers of activated, inflammatory T cells and massively reduced numbers of apoptotic CD4⁺ T cells, compared to healthy controls. This finding might explain the mechanism and success of dietary intervention therapy in CD patients, where uncontrolled activated diet-reactive CD4⁺ T cell will be starved by an elemental diet of low antigenicity.

Based on their findings and critical review of current knowledge on dietary antigens, the authors proposed a new model of how the intestinal immune system maintains a balance between the recognition and tolerance of dietary antigens at the same time. Their proposal is that the continuous uptake of dietary antigens by Peyer’s patches in the healthy gut results in increasing activation of CD4⁺ T cells until hyper-activated lymphocytes undergo apoptosis. However, in patients with Crohn’s disease this mechanism is disturbed, an observation that might facilitate the understanding of the benefits of dietary intervention therapy.