CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.
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.
Fletcher
Jean M
JM
School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
Lonergan
Roisin
R
Costelloe
Lisa
L
Kinsella
Katie
K
Moran
Barry
B
O'Farrelly
Cliona
C
Tubridy
Niall
N
Mills
Kingston H G
KH
D000241:Adenosine / Q000276:immunology / Q000378:metabolism; D000328:Adult; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001081:Apyrase / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine