MicroRNA-21 Regulates Diametrically Opposed Biological Functions of Regulatory T Cells

Abstract

Regulatory T cells (Tregs) are considered important for controlling the onset and development of autoimmune disease. Although studies have shown that miR-21 is expressed at higher levels in Treg cells, it remains largely elusive whether miR-21 regulates the immune-suppressive function of Tregs. In the current study, we generated mice lacking miR-21 specifically in their Tregs and investigated the role of miR-21 in regulating Treg function both in vitro and in vivo. Our study revealed that Tregs lacking miR-21 exhibit normal phenotype and unaltered function in suppressing T cell proliferation and dendritic cell activation in vitro. However, compared with miR-21-sufficient Tregs, they produce significant more IL-17 and IL-10 when under pathogenic Th17-priming condition. Adenoviral delivery of miR-21 into Treg cells is able to reduce the expression of both IL-17 and IL-10. Mechanistic study revealed that miR-21 down-regulates IL-10 expression through direct targeting of IL-10, and suppresses reprogramming of Tregs into IL-17-secreting cells through down-regulating Stat3 activity. However, we detected no significant or marginal difference in the development of various autoimmune diseases between wild type mice and mice with Treg-specific deletion of miR-21. In conclusion, our study demonstrated that miR-21 in Tregs regulates diametrically opposed biological Treg functions and is largely dispensable for the development of autoimmune disease.

Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function

“…While some studies show that transfection of naïve human CD4 T cells with miR-21 is sufficient to induce Treg development by increasing Foxp3, TGFb, and IL-10, another study found that miR-21 promotes RORgt and suppresses Foxp3 and IL-10 (180, 186, 187). Indeed, Treg specific depletion of miR-21 in mice induced the expression of both IL-17 and IL-10 indicating that miR-21 may play a role in opposing pathways (184). In line with these opposing observations, increased miR-21 expression inhibited FOXP3+ Tregs in human gastric cancer (188) whereas it induced FOXP3 in human and mouse autoimmunity (182,183).…”

“…miR-21 acts indirectly to positively regulate Foxp3 expression (180); however, in autoimmunity, reduced miR-21 expression is correlated with increased STAT3 and reduced STAT5 and Foxp3 expression (26,(181)(182)(183). miR-21 directly targets STAT3 resulting in its downregulation and subsequently reduces effector molecules IL-17 and IL-22 (182,184). Maresin 1 (MaR1) and the EGF/c-Jun pathway have both been shown to induce miR-21, restore Treg : Teff ratios through FOXP3 induction, and reduce autoimmunity (183,185).…”

The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Rheumatoid Arthritis and Osteoarthritis

“…Moreover, it could be associated with T cell differentiation, due to its interaction with STAT3. This inhibits the transformation of Tregs into the cells secreting IL-17 [102]. Similarly, another study demonstrated that Maresin1, a macrophage-derived mediator, suppressed Th17 and enhanced the Treg differentiation by miR-21 overexpression [103].…”