Immunomodulatory mechanisms of the gut microbiota and metabolites on regulatory T cells in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease, in which the abnormal activation and proliferation of effector T cells play a pivotal role in its pathogenesis. Regulatory T cells (Tregs) are a unique subset of immune cells with immunosuppressive functions, which help to inhibit the differentiation and proliferation of effector T cells in RA and maintain immune tolerance. The interaction between gut microbiota and immune cells has long been a research hotspot in autoimmune diseases. Although gut microbiota metabolites are considered to regulate the host's immune system as a bridge of the gut-joint axis, how gut microbiota acts on immunosuppressive Tregs remains unclear. This review summarizes that how the gut microbiota directly or indirectly (via metabolites) enhances the immunosuppressive capacity of Tregs. This enhancement is primarily achieved through pathways such as promoting the induction of Tregs, upregulating the expression of characteristic transcription factors of Tregs, and facilitating their secretion of anti-inflammatory cytokines, thereby ameliorating the inflammatory microenvironment and subsequently improving autoimmune conditions in RA.

Keywords: autoimmune; gut microbiota; metabolites; regulatory T cells; rheumatoid arthritis.

Figure 1

Pathologically, APCs (DCs and macrophages) present antigens to CD4+ T cells, which abnormally activate their differentiation into Th1 and Th17 subtypes. These two subtypes secrete pro-inflammatory factors such as IFN-γ and IL-17, which in turn lead to the proliferation of fibroblast-like synoviocytes, and ultimately bone destruction. In contrast, Treg cells inhibit abnormal antigen presentation by competitively binding to CD80/CD86 and MHC on the DCs surface; secreting anti-inflammatory factors and inhibiting Th proliferation through the CD39/CD73/A2a adenosine pathway. (DCs, Dendritic Cells;MHC, Major Histocompatibility Complex;TCR, T Cell Receptor; FOXP3, Foxhead Pox protein 3; HDAC, Histone deacetylase; CNS, conserved non-coding sequences; CTLA4, Cytotoxic T-Lymphocyte Associated protein 4;GITR, Glucocorticoid-induced TNFR-related protein; LAP, latency-associated peptide; Lag-3, lymphocyte-activation gene 3; PD-1, programmed cell death protein 1; NRP1, Neuropilin-1;RANK, receptor activator of NF- κB; RANKL, receptor activator of NF- κB ligand).

Figure 2

The intestinal microbiota and their metabolites can enhance the homeostasis and functionality of Tregs through direct cellular contact-mediated mechanisms. Concurrently, they promote the differentiation of regulatory DCs, which subsequently stimulate CD4+ T cells to preferentially differentiate into Tregs. Distinct arrow colors are utilized to delineate the differential regulatory pathways mediated by specific microbial taxa or metabolites. (TLR, Toll-like receptor; CSGG, cell surface glucan/galactan; PSA, polysaccharide A; PD-1, programmed cell death protein 1; GPR, G-protein-coupled receptors; TGR-5, Takeda G protein-coupled receptor 5; FXR, Farnesoid X Receptor).

Figure 3

Factors influencing the interaction between the gut microbiota and Tregs.