Focus on Inflammatory Disease

Influence of nutrient-derived metabolites on lymphocyte immunity

Journal name:
Nature Medicine
Year published:
Published online


Organisms need to protect themselves against potential dangers from their surroundings, yet they require constant and intimate interactions with the same environment for their survival. The immune system is instrumental for protection against invading organisms and their toxins. The immune system consists of many cell types and is highly integrated within other tissues. Immune activity is particularly enriched at surfaces that separate the host from its environment, such as the skin and the gastrointestinal tract. This enables protection at sites directly at risk but also enables environmental factors to influence the maturation and function of immune structures and cells. Recent work has indicated that the diet in particular is able to influence the immune system and thus affect the development of inflammatory disease. This review aims to highlight recent work on how external factors, with a focus on those derived from the diet such as vitamin A, can have a direct or indirect deterministic influence on the activity and function of immunity.

At a glance


  1. Developmental time frame of lymphoid tissue organogenesis.
    Figure 1: Developmental time frame of lymphoid tissue organogenesis.

    (a) Prominent factors that influence immunity are dietary micronutrients and the vitamin D generated in our skin under the influence of sunlight. They affect cells of the immune system and the development of immune clusters such as lymph nodes, located throughout the body, and Peyer's patches in the small intestine, localized under the intestinal epithelial layer in close proximity to the gut contents. In the lymph nodes, stroma and immune cells encounter the local immune cells and nutrients and microbial products previously filtered through the epithelial surfaces, which are delivered via the blood and lymph. (b) The development of lymph nodes and Peyer's patches starts before birth through interactions between lymphoid tissue inducer (LTi) cells, lymphoid tissue initiator (LTin) and organizer (LTo) cells. During this time window, vitamin A has an important role in determining the ultimate size of the developing lymph node. Also before birth, intraepithelial lymphocytes occupy the epithelial barriers. They are maintained at these sites in adulthood by signals from arylhydrocarbons and remain in close contact with the epithelial cells. At the time of birth, small lymphoid clusters called cryptopatches appear in the intestine. These expand rapidly, requiring signals mediated by arylhydrocarbons, as well as the microbiota which is encountered in the first period of life, to mature into isolated lymphoid follicles. Adapted with permission from ref. 135, Nature Publishing Group.

  2. Pathways involved in nutrient signaling in some lymphocytes.
    Figure 2: Pathways involved in nutrient signaling in some lymphocytes.

    Nutrient metabolites are absorbed via the intestinal lumen and transported via the blood. Often additional metabolic processing is required, in the liver and kidneys, to generate bioactive compounds. The nuclear receptors they stimulate are located in the cytoplasm and translocate to the nucleus upon ligand binding, bind to defined response elements, dependent upon nuclear cofactors (as shown) enabling the transcription of gene products, including members of the cytochrome P450 family (Cyp). (a) The vitamin A bioactive compounds 9-cis-retinoic acid (9cRA) and all-trans-RA (ATRA) can bind to three isoforms of the retinoic acid receptor (RAR), which can form heterodimers with the retinoic X receptor (RXR), which is also present in three isoforms. The isoforms can be differentially expressed in different cell types and bind to retinoic acid response elements (RAREs). (b) Vitamin D, mainly derived from sun-exposed skin, undergoes metabolic processing in liver and kidney to generate bioactive compounds, especially 1,25-(OH)2D3. It binds to the vitamin D receptor (VDR), which can also partner with the RXR isoforms and bind to vitamin D response elements (VDREs). (c) Arylhydrocarbons such as 6-formylindolo(3,2-b)carbazole (FICZ) and 3,3′-diindolylmethane (DIM), derived from food and microorganisms, bind to the arylhydrocarbon receptor (AhR). Upon translocation to the nucleus AhR partners with the arylhydrocarbon nuclear transporter (ARNT) and bind to xenobiotic response elements (XREs). HAT, histone acetyltransferase; HDAC, histone deacetylase; NCoR, nuclear receptor co-repressor 1; HSP90, heat-shock protein of 90 kDa; ara9, arylhydrocarbon receptor-associated protein; p160, coactivator (e.g., TIF2/RAC3/SRC-1); p23, prostaglandin E synthase 3 (Ptges3).


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  1. Laboratory for Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.

    • Marc Veldhoen &
    • Cristina Ferreira

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