CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.

J Immunol 2009 Dec 16;183(11):7602-10. Epub 2009 Nov 16.

School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.

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(+)CD25(high)CD39(+) and CD4(+)CD25(high)CD39(-) T cells suppressed proliferation and IFN-gamma production by responder T cells, only the CD4(+)CD25(high)CD39(+), which were predominantly FoxP3(+), suppressed IL-17 production, whereas CD4(+)CD25(high)CD39(-) T cells produced IL-17. An examination of T cells from multiple sclerosis patients revealed a normal frequency of CD4(+)CD25(+)CD127(low)FoxP3(+), but interestingly a deficit in the relative frequency and the suppressive function of CD4(+)CD25(+)CD127(low)FoxP3(+)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.

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http://dx.doi.org/10.4049/jimmunol.0901881DOI Listing
December 2009
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J. Clin. Invest. 2008

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