CD39+Foxp3+ Regulatory T Cells Suppress Pathogenic Th17 Cells and Are Impaired in Multiple Sclerosis

Abstract

Despite the fact that CD4+CD25+Foxp3+ regulatory T cells (Treg cells) play a central role in maintaining self-tolerance and that IL-17-producing CD4+ T cells (Th17 cells) are pathogenic in many autoimmune diseases, evidence to date has indicated that Th17 cells are resistant to suppression by human Foxp3+ Treg cells. It was recently demonstrated that CD39, an ectonucleotidase which hydrolyzes ATP, is expressed on a subset of human natural Treg cells. We found that although both CD4+CD25highCD39+ and CD4+CD25highCD39− T cells suppressed proliferation and IFN-γ production by responder T cells, only the CD4+CD25highCD39+, which were predominantly FoxP3+, suppressed IL-17 production, whereas CD4+CD25highCD39− T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4+CD25+CD127lowFoxP3+, but interestingly a deficit in the relative frequency and the suppressive function of CD4+CD25+CD127lowFoxP3+CD39+ Treg cells. The mechanism of suppression by CD39+ Treg cells appears to require cell contact and can be duplicated by adenosine, which is produced from ATP by the ectonucleotidases CD39 and CD73. Our findings suggest that CD4+CD25+Foxp3+CD39+ Treg cells play an important role in constraining pathogenic Th17 cells and their reduction in multiple sclerosis patients might lead to an inability to control IL-17 mediated autoimmune inflammation.

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

“…With regard to Treg cells, CD39 is constitutively expressed on ϳ50% of human CD25ϩFoxP3ϩ nTreg cells in healthy controls (33). The percentage of CD39ϩ cells among CD4ϩCD25ϩFoxP3ϩ T cells was signifi- …”

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

“…Expression of the ectonucleotidase CD39 by Foxp3+ T regulatory cells (Treg) has previously been reported to be associated with inhibition of IL-17A production (36,39,40). Analysis of ex vivo expression of CD39 demonstrated a significantly higher frequency of CD3+CD39+ T cells in the peripheral blood of healthy donors as compared to severe asthmatics (p=0.003).…”

“…Analysis of ex vivo expression of CD39 demonstrated a significantly higher frequency of CD3+CD39+ T cells in the peripheral blood of healthy donors as compared to severe asthmatics (p=0.003). CD39 can be expressed on both CD4+ memory and Foxp3+ T cells (36,39), so we further analysed expression on Foxp3+ and Foxp3-populations. A significantly higher frequency of CD39 expressing cells was detected in both CD3+Foxp3-and CD3+Foxp3+ T cells in the non-asthmatic donors as compared to the severe asthmatics ( Figure 4A), in contrast to the higher IL-17A synthesis observed in the patients.…”

“…The ectonucleotidase CD39, which is expressed by memory T cells as well as Foxp3+ regulatory T cells has previously been reported to inhibit IL-17A synthesis (36,39,40). In the present study, treatment with 1,25(OH)2D3 increased the mean intensity of CD39 expression by human CD4+ T cells, while the CD39 antagonist POM-1 partially abrogated 1,25(OH)2D3 -mediated inhibition of the IL-17A production, supporting a mechanistic role for this pathway but not excluding others.…”

“…Finally, in an attempt to elucidate possible mechanisms of the effect of 1,25(OH)2D3 in altering IL-17A production, we measured its effects on the expression of the ectonucleotidase CD39, elevated expression of which has previously been reported to be associated with inhibition of IL-17A production in autoimmune disease (36). We hypothesised that dexamethasone, but not 1,25(OH)2D3 reduces CD39 expression on blood T cells and that inhibition of its ectonucleotidase activity abolishes Nanzer et al 6 any effects of 1,25(OH)2D3 on IL-17A expression.…”