Naturally occurring CD4+
regulatory T cells (nTregs) play crucial roles in controlling autoimmune disease by maintaining immunological homeostasis and self-tolerance (1
). Adoptive transfer of nTregs has been proven to prevent many autoimmune diseases; however, transfer of nTregs once the disease is established is less predictable. In lupus, their effect was only modest (2
). In collagen-induced arthritis (CIA), nTreg transfer could prevent but was unable to modify established disease (3
). The reasons for lack of effect are poorly understood and may include instability of Foxp3 in an inflammatory milieu (5
), conversion to proinflammatory effector cells (5
) or an acquired resistance of T effector cells to Tregs (7
Recent studies have documented the instability of nTregs in the presence of certain proinflammatory cytokines. For instance, we and others (5
) have recently reported that TCR-stimulated nTregs can be converted to Th17 cells in the presence of IL-6 in vitro. Strong TCR stimulation also drives the conversion of nTregs to Th1 cells (8
). Additionally, decreased Foxp3 expression can cause immune disease by subverting the suppressive function of nTregs and converting them into Th2 cells (9
). Moreover, the suppressive activities of nTregs can be abrogated by IL-6 (10
). Therefore, it is desirable to find an approach that can sustain the stability and functionality of nTregs in the inflammatory condition.
retinoic acid (atRA), the major vitamin A metabolite, has been proven to not only enhance the de novo generation of naive CD4+
cells to Foxp3+
Tregs but also suppress de novo differentiation of naive CD4+cells to Th17 cells (11
). We have addressed in this paper the effects of atRA on nTregs. We found that atRA not only maintains the phenotypic stability of nTregs but also sustains their functional activities in the presence of IL-6. Pretreatment of nTregs with atRA can downregulate IL-6R expression and IL-6R signaling, therefore restraining nTregs to Th17 conversion and sustaining Foxp3 expression of nTregs. Of note, we found that adoptive transfer of nTregs treated with atRA to established CIA markedly suppressed the progression and ameliorated the severity of arthritis. More importantly, atRA can alter the stability and function of nTregs from autoimmune arthritic mice, implicating that this strategy may have an important clinical value.