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Development and maintenance of intestinal regulatory T cells

Key Points

  • Intestinal regulatory T (Treg) cells consist of at least three subpopulations: IL-10+RORγt+ microbiota-stimulated peripherally derived Treg (pTreg) cells, RORγtNRP1 dietary antigen-stimulated pTreg cells and GATA3+ thymus-derived Treg (tTreg) cells.

  • Treg cell subpopulations have complementary functions, including the maintenance of homeostasis against the microbiota and dietary components in the steady state and the suppression of inflammatory responses.

  • The gut microbiota influences the differentiation, accumulation, function and T cell receptor (TCR) repertoire of colonic Treg cells. In turn, the host–microbiota symbiotic relationship in the gut relies on Treg cells that control antigen-specific responses directed to gut microorganisms.

  • Microbial and dietary metabolites, such as short-chain fatty acids, vitamins and amino acids affect the differentiation and the survival of Treg cells.

  • Treg cell generation involves several mechanisms that function in a cell-intrinsic and cell-extrinsic manner. Macrophages, innate lymphoid cells and dendritic cells are strategically positioned beneath the intestinal epithelial cells to sense the types and the features of the intraluminal microorganisms and dietary components and to coordinately promote T cell homeostasis in the intestines.

Abstract

Gut-resident forkhead box P3 (FOXP3)+CD4+ regulatory T cells (Treg cells) are distinct from those in other organs and have gut-specific phenotypes and functions. Whereas Treg cells in other organs have T cell receptors (TCRs) specific for self antigens, intestinal Treg cells have a distinct set of TCRs that are specific for intestinal antigens, and these cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms. The differentiation, migration and maintenance of intestinal Treg cells are controlled by specific signals from the local environment. In particular, certain members of the microbiota continuously provide antigens and immunoregulatory small molecules that modulate intestinal Treg cells. Understanding the development and the maintenance of intestinal Treg cells provides important insights into disease-relevant host–microorganism interactions.

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Figure 1: Stepwise induction of tTreg cells and pTreg cells.
Figure 2: Proposed mechanisms for the accumulation of colonic Treg cells.
Figure 3: Three subpopulations in the intestinal Treg cells.
Figure 4: Cellular and molecular mechanisms for the induction of intestinal pTreg cells.

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Acknowledgements

This work was supported by CREST and the Practical Research Project for Intractable Diseases from the Japan Agency for Medical Research and Development (AMED), the Suzuken Memorial Foundation, the Nakajima Foundation, the Takeda Science Foundation, the Mishima Kaiun Memorial Foundation, Keio University Medical Science Fund and the Uehara Memorial Foundation.

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Correspondence to Kenya Honda.

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Glossary

DEREG mice

(Depletion of regulatory T cells mice). Transgenic mice expressing a diphtheria toxin receptor under the control of the forkhead box P3 (Foxp3) gene promoter, using a bacterial artificial chromosome. Administration of diphtheria toxin to these mice results in the conditional deletion of FOXP3+ regulatory T cells.

Foxp3GFP mice

Mice expressing a chimeric GFP–forkhead box P3 (FOXP3) fusion protein from the Foxp3 locus. All FOXP3+ regulatory T cells in these mice express GFP. Note that the modified Foxp3 allele functions as a genetic susceptibility locus.

Immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome

(IPEX syndrome). A primary immunodeficiency caused by mutations in forkhead box P3 (FOXP3). Patients with this syndrome have defective functional regulatory T cells and develop insulin-dependent diabetes, thyroiditis, eczema, haemolytic anaemia and inflammatory bowel disease. In the absence of a bone marrow transplant, these patients die at an early age.

T follicular helper cell

(TFH cell). A CD4+ T helper cell lineage that is essential for the induction of class switching in the germinal centres of secondary lymphoid follicles during antibody responses to T cell-dependent antigens. These cells support the differentiation of antigen-specific B cells into memory B cells or plasma cells.

Germ-free mice

Mice that are completely free of the presence of other organisms. Germ-free mice are produced by hysterectomy rederivation and must be maintained in sterile isolators under very strict handling procedures to keep them germ-free.

Antibiotic-treated mice

A generally accessible alternative to using germ-free mice in which the microbiota of conventional mice is depleted by using a combination of broad-spectrum antibiotics. A combination of ampicillin, vancomycin, neomycin and metronidazol is frequently used for this purpose. However, any antibiotic treatment protocol tested so far achieves only an incomplete depletion of the microbiota.

Specific pathogen-free mice

(SPF mice). Mice that harbour a complex diversity of commensal microorganisms but are free of a specific list of organisms. The list of organisms typically includes disease-causing pathogens that can affect mouse health and research outcomes, as well as opportunistic organisms (pathobionts) that typically do not cause illness in normal, healthy mice.

Keratin 14-transgenic mice

(K14-transgenic mice). Mice that are generated by crossing mice lacking all MHC class II-associated molecules with transgenic mice in which these molecules are expressed under the control of the keratin promoter. In these mice, MHC class II-associated antigens are expressed solely by epidermal cells and cortical thymic epithelial cells.

T regulatory type 1 cells

(TR1 cells). A subset of forkhead box P3 (FOXP3)CD4+ regulatory T cells that secrete high levels of interleukin-10 (IL-10). TR1 cells were originally described as a subset of naive CD4+ T cells activated ex vivo in the presence of IL-10 or by IL-10-conditioned dendritic cells. TR1 cells mediate suppression by a cell contact-independent, cytokine- dependent mechanism that involves IL-10 and transforming growth factor-β.

CD4+CD8αα+ regulatory T cells

Unlike most T cells in the periphery, a substantial fraction of intestinal mucosal T cells express the homodimeric form of CD8 (CD8αα), together with CD4. CD4+CD8αα+ T cells show regulatory characteristics and secrete interleukin-10. These cells have an oligoclonal T cell receptor repertoire directed towards intestinal commensal bacteria and their frequency is decreased in germ-free mice and in patients with inflammatory bowel disease.

Altered Schaedler flora

(ASF). A standard enteric flora that were selected for their dominance and persistence in the normal microflora of mice. ASF contains eight species. The 16S gene sequence of ASF360 is identical to Lactobacillus acidophilus, whereas that of ASF361 is similar to that of Lactobacillus murinus and Lactobacillus animalis. ASF519 is related to Bacteroides distasonis, whereas ASF356, ASF502 and ASF492 fall within Clostridia cluster XIV. ASF457 is a spiral-shaped bacterium that clusters with the Flexistipes species, whereas ASF500 is not closely related to any of the sequences in the database.

Outer membrane vesicles

(OMVs). Spherical buds of the outer membrane filled with periplasmic content produced by Gram-negative bacteria. The production of OMVs allows bacteria to interact with their environment, thereby having an important role in bacterial physiology as well as in virulence and commensalism. As commensal bacteria generally do not make intimate contact with host cells, OMVs appear to provide a suitable mechanism for members of the microbiota to deliver molecules to the host.

Dysbiosis

A condition with imbalance in the composition of the bacterial microbiota; this includes an outgrowth of potentially pathogenic bacteria and/or a decrease in bacterial diversity and bacteria beneficial to the host.

Faecal microbiota transplantation

(FMT). A process of transplantation of a diverse intestinal microbial community from a healthy individual into a patient through infusion of stool by orogastric tube, enema, colonoscopy or oral administration of a capsule containing freeze-dried material.

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Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16, 295–309 (2016). https://doi.org/10.1038/nri.2016.36

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