TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis

Abstract

The human gastrointestinal tract has an enormous and diverse microbial community, termed microbiota, that is necessary for the development of the immune system and tissue homeostasis. In contrast, microbial dysbiosis is associated with various inflammatory and autoimmune diseases as well as neurological disorders in humans by affecting not only the immune system in the gastrointestinal tract but also other distal organs. FOXP3⁺ regulatory T cells (Tregs) are a subset of CD4⁺ helper T cell lineages that function as a gatekeeper for immune activation and are essential for peripheral autoimmunity prevention. Tregs are crucial to the maintenance of immunological homeostasis and tolerance at barrier regions. Tregs reside in both lymphoid and non-lymphoid tissues, and tissue-resident Tregs have unique tissue-specific phenotype and distinct function. The gut microbiota has an impact on Tregs development, accumulation, and function in periphery. Tregs, in turn, modulate antigen-specific responses aimed towards gut microbes, which supports the host-microbiota symbiotic interaction in the gut. Recent studies have indicated that Tregs interact with a variety of resident cells in central nervous system (CNS) to limit the progression of neurological illnesses such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. The gastrointestinal tract and CNS are functionally connected, and current findings provide insights that Tregs function along the gut-brain axis by interacting with immune, epithelial, and neuronal cells. The purpose of this study is to explain our current knowledge of the biological role of tissue-resident Tregs, as well as the interaction along the gut-brain axis.

Keywords: central nervous system; gastrointestinal tract; gut–brain axis; microbiota; neuroimmune; regulatory T cell.

Figure 1

Schematic overview showing the interaction between the GI tract and the CNS through the ‘gut-brain axis’. The central nervous system is connected with the intestine by the peripheral nerves for reciprocal interaction and tissue homeostasis in which immune cells including Tregs are involved in this entangled inter-organ communication. Immunological factors, produced by gut immune cells, can regulate the nerves innervating to the intestine, eventually affecting the CNS function. In the opposite direction, neurological factors such as neurotransmitters can act on the gut immune system. Furthermore, the gut microbiome can modulate the gut-brain axis by microbe-derived molecules. In these processes, Tregs may act as a critical regulator of pathophysiology along the gut-brain axis. (All figures in the review were created with BioRender.com).

Figure 2

The three main subsets of FOXP3⁺ Tregs are controlled by host and environmental factors in the intestine. 1) The FOXP3⁺ RORγt^- Tregs are present mainly in the small intestine, mainly induced by dietary antigens. GATA3⁺ Tregs are thymic origin Tregs with high level of ST2, thus these cells can respond to IL-33, secreted from IECs in response to tissue damage. Moreover, OX40 expression on GATA3⁺ Tregs supports the accumulation of Tregs in the colon and OX40 is required for the Tregs-mediated restriction of effector T cells (Teff). 2) RORγt⁺ Tregs constitute the main colonic Tregs subset, promoted by the microbiota. SCFAs, secondary BAs and AhR ligands can induce Tregs differentiation, however the effect of these metabolites on different Tregs subsets are not known, except a recent finding showing that BAs induce RORγt⁺ Tregs. 3) CD103⁺ DCs induce the differentiation of Tregs in a TGF-β-dependent manner and suppress Th17 cells. These functions of DCs are regulated by αVβ8 integrin-mediated activation of latent TGF-β1 and RALDH-mediated metabolizing of vitamin A into RA. ILC3s, triggered by microbe-activated macrophages, promote Tregs in the intestine through IL-2 or CSF2 production. These microbiota induced Tregs, either through microbial metabolites or other immune cell types are essential for the maintenance of immune homeostasis. 4) The crosstalk between intestinal epithelium and Tregs are essential for intestinal homeostasis. Tregs can interact directly with ISCs via MHCII molecule and promote ISCs renewal by IL-10 signaling. IECs-derived IL-18 is an important regulator of Treg-mediated suppression of intestinal inflammation.

Figure 3

Characteristics of CNS-resident Tregs and their interaction with other CNS cells. T cells including Tregs exist in the meningeal space and the brain parenchyma in both physiological and pathological conditions. In disease status, Tregs interact with CNS cells such as neural stem cells (NSCs), oligodendrocytes, microglia, astrocytes, and neurons to modulate the pathology of CNS insults. CNS-resident Tregs express a high level of Treg markers such PD-1 along with neuronal receptors including 5-HT7. CCN3, cellular communication network factor 3; SPP1, osteopontin; AREG, amphiregulin; SIRPα, signal regulatory protein alpha; 5-HT7, serotonin receptor 7; ST2, interleukin-1 receptor-like 1; PD-1, programmed cell death 1; CTLA4, cytotoxic T-lymphocyte-associated protein 4; GITR, glucocorticoid-induced TNFR-related protein.

Figure 4

Possible model of crosstalk between intestinal Tregs and gut-innervating neurons. External neuronal cells from the peripheral nervous system innervate to the intestine, and neurons in the enteric nervous system exist in the colonic myenteric and submucosal plexus. Neuronal factors, released from the nerve terminal, are involved in the regulation of intestinal Tregs. A neurotransmitter acetylcholine (Ach) activates colonic antigen presenting cells, which may support the development of pTregs in the intestine. Vasoactive intestinal peptide (VIP) enhances the proliferation of Tregs and calcitonin gene-related peptide (CGRP) promotes the differentiation of Tregs. Cytokines such as IL-6, produced by neuronal cells, regulate the induction of RORγt⁺ Tregs. It is expected that Tregs-derived molecules can signal to neuronal cells to modulate their function, which have to be further elucidated.