Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development

Abstract

Modern industrial practices have transformed the human diet over the last century, increasing the consumption of processed foods. Dietary imbalance of macro- and micro-nutrients and excessive caloric intake represent significant risk factors for various inflammatory disorders. Increased ingestion of food additives, residual contaminants from agricultural practices, food processing, and packaging can also contribute deleteriously to disease development. One common hallmark of inflammatory disorders, such as autoimmunity and allergies, is the defect in anti-inflammatory regulatory T cell (Treg) development and/or function. Treg represent a highly heterogeneous population of immunosuppressive immune cells contributing to peripheral tolerance. Tregs either develop in the thymus from autoreactive thymocytes, or in the periphery, from naïve CD4⁺ T cells, in response to environmental antigens and cues. Accumulating evidence demonstrates that various dietary factors can directly regulate Treg development. These dietary factors can also indirectly modulate Treg differentiation by altering the gut microbiota composition and thus the production of bacterial metabolites. This review provides an overview of Treg ontogeny, both thymic and peripherally differentiated, and highlights how diet and gut microbiota can regulate Treg development and function.

Keywords: gut microbiota; nutrition; nutritional immunology; regulatory T cell; thymopoiesis; tolerance.

Figure 1

Impact of dietary components on Treg development. Dietary components have varying effect on Treg development, with dietary fats inducing Treg by modulating metabolic activity or through the activation of nuclear receptors (NRs) such as PPARδ. Dietary protein generally support Treg development, with L-citrulline enhancing the histone deacetylase (HDAC) Sirt1 to promote Treg development. Dietary carbohydrates, including feruloylated oligosaccharides and glucose act on conventional dendritic cell (cDC) and CD103⁺ DC, boosting their production TGF-β and retinoic acid (RA), respectively, to promote Treg. Vitamin (Vit) A is a substrate for RA production required for Treg induction while vitamin B7 and D finetune mTOR-related metabolic signals or bind to NRs to support Treg induction. Dietary trace elements like selenium (Se) and zinc (Zn) are supportive toward Treg development with unknown mechanisms. The food additives TiO₂ and salt, and the contaminant biphenol A (BPA) exhibit mixed/complex regulatory patterns toward Treg development while pesticides like chlorpyrifos suppressed Treg development. Dietary components promoting Treg development are colored in green, the ones impeding in blue, and the ones with mixed effect in yellow.

Figure 2

Impact of gut bacteria on regulatory T cell development and function. Microbiota-derived metabolites can regulate Treg development and function via distinct mechanisms. Indoles and secondary bile acids (BAs) can bind to nuclear receptors (NRs) to promote Foxp3 expression and Treg induction. Short-chain fatty acids (SCFAs) can activate G protein-coupled receptors (GPCRs) to promote Treg directly via inhibition of histone deacetylase (HDAC) activity, or indirectly, by enhancing retinal dehydrogenases (RALDH) and retinoic acid (RA) production by CD103⁺ DCs and epithelial cells. Alternatively, SCFA are directly taken up by cells, including regulatory B cells (Bregs) and conventional DCs (cDCs) to promote expression of Treg-inducing cytokines TGF-β and IL-10. SCFA uptake by T cells can also directly promote Treg induction by increasing mitochondrial activity. Bacterial pathogen associated molecular patterns (PAMPs) can also promote Treg via activation of toll-like receptors (TLR). Bacteroides fragilis-derived polysaccharide A (PSA) promote Treg via TLR signalling on DCs, promoting IL-10 production, as well as Treg-intrinsic TLR2 signals. Extracellular vesicles (EVs) are PAMPs that can bind to TLR and C-lectin expressed by gut DCs and epithelial cells, triggering the release of Treg-inducing cytokines IL-10 and TGF-β.