Type 3 regulatory T cells at the interface of symbiosis

Abstract

The mammalian gastrointestinal tract accommodates trillions of bacteria, many of which provide beneficial effects to the host, including protection from pathogenic microorganisms and essential metabolites. However, the intestinal immune system needs to adapt to the constantly fluctuating microbial environment at mucosal surfaces in order to maintain homeostasis. In particular, the gut microbiota induces the differentiation of effector Th17 cells and regulatory T cells (Tregs) that express RORγt, the master regulator of antimicrobial type 3 immunity. RORγt Tregs constitute a major population of colonic Tregs that is distinct from thymusderived Tregs and require bacterial antigens for differentiation. The balance between Th17 cells and RORγt Tregs, that is, the tone of the local type 3 immune response, is regulated by the vitamin A metabolite retinoic acid produced by the host. Furthermore, Th17 cells and RORγt Tregs regulate intestinal type 2 immune responses, explaining how bacteria block allergic reactions. Here, we review the cellular and molecular mechanisms involved in the differentiation, regulation and function of RORγt (type 3) Tregs, and discuss the multiple equilibria that exist between effector T cells and Tregs, as well as between different types of immune responses, which are necessary to maintain homeostasis and health.

The gut-liver axis in liver disease: Pathophysiological basis for therapy

“…35 In the intestine one can also find innate lymphoid cells which can release type 1, 2 and 3 cytokines in a rapid response to infection before the action of adaptive T cells. 36,37 Hence the whole intestinal barrier is formed in response to the microbiota by the coordinated action of structural elements (mucus, epithelial cells), immune cells (intraepithelial and lamina propria immune cells) and soluble mediators (IgA, antimicrobial peptides). Any changes in these elements can alter the intestinal barrier.…”

“…These can have several activities on both the intestinal epithelial barrier, the immune system and the microbiota. SCFAs, for instance, have been shown to control the differentiation of several immune cells and in particular T regulatory cells, 36 the microbicidal activity of macrophages 44 and several other immune cell functions. 45 The fibres and their postbiotics can also impact on the brown versus white adipose tissue ratio.…”

Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk

“…Mucin glycosylation is also under the control of the ratio Bacteroides:Firmicutes [ 115 ]. Secondary metabolites are able to modulate other function, namely the differentiation of immune cells, i.e., T regulatory cells [ 116 ], macrophages, and microbicidal activity [ 117 ]. Effects of secondary metabolites are possible upon fiber metabolization, which involve white and brown adipose ratio [ 118 ].…”

Regulatory B and T lymphocytes in multiple sclerosis: friends or foes?

“…In addition, CD8(+) Tregs (Tr2) and IL-17-producing Tregs that share some common features with Tr1 also exist [ 57 ]. iTregs-expressing RORγt, which is the master regulator of antimicrobial type 3 immunity are termed type 3 Tregs (Tr3) [ 58 , 59 ]. These cells constitute the major population of colonic Tregs, require bacterial antigens for differentiation and are distinct from thymus-derived Tregs.…”