The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome

Abstract

T-helper 17 (Th17) and T-regulatory (Treg) cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6, and all-trans retinoic acid. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate and downstream adaptive immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease.

Keywords: T-helper 17 cells; T-regulatory cells; gut microbiome; inflammatory bowel disease; intestinal homeostasis.

Figure 1

Cytokine milieu orchestrates Treg and Th17 cell plasticity. Th17 cells lose stability in the absence of TGFβ and presence of IL-12, IL-23, and IL-1β, favoring IFNγ expression and differentiation into Th1/Th17 cells that produce both Th1 (e.g., IFNγ) and Th17 (e.g., IL-17, IL-22) cytokines. Further augmentation of IL-12 can fully convert Th1/Th17 cells into Th1 cells, whereas this process can be reverted by either TGFβ and IL-6 or in the absence of retinoic acid (RA) in favor of Th1/Th17 or Th17 cells, respectively. Alternatively, the abundance of TGFβ in the absence of IL-6 drives Th17 cells toward regulatory phenotypes, such as either RORγt⁺Foxp3⁺ Treg/Th17 cells or Foxp3⁻ Tr1 cells. If proinflammatory cytokines are present, including either IL-6 or IL-1β and IL-6, Foxp3⁺ Tregs have the ability to transdifferentiate into either Th17 or Treg/Th17 cells, respectively.

Figure 2

Impact of the gut microbiota on Treg and Th17 immune responses. Colonization with segmented filamentous bacteria (SFB) occurs by intimate attachment to the intestinal epithelium and promotes the development of Th17 cells via intestinal epithelial cell (IEC)-derived cytokines, serum amyloid A (SAA), as well as antigen presentation by dendritic cells (DCs). Adhesion of SFB to IEC can potentially generate a circuit, wherein DC-derived IL-23 stimulates IL-22 production by type 3 innate lymphoid cells (ILC3), which in turn induces SAA from IEC and can lead to Th17 cell differentiation. Conversely, colonization of beneficial commensal bacteria induces de novo generation of Tregs and downregulates Th17 immune responses. Commensal bacteria, including most Clostridia species, produce short-chain fatty acids, i.e., butyrate, which participates in the de novo generation of Tregs by suppressing proinflammatory cytokines, by promoting RA production from DCs, and by inducing Foxp3 transcription. Among different Bacteroides fragilis strains, those expressing polysaccharide A (PSA) mediate the generation of Tregs via TLR2, while those secreting B. fragilis toxin (BFT) alter the function of IEC tight junctions. Upon disruption of barrier function, dissemination of microbial products, recognized by microbe-associated molecular patterns (MAMPs), occurs and activates the IL-23 pathway, resulting in subsequent barrier repair and stimulation of Th17 immune responses.