Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

CD39/ENTPD1 is a prototypic member of the ectonucleoside triphosphate diphosphohydrolase (ENTPDase) family on cell surface. CD39 has been reported to be a marker of regulatory immune cells and catalyzes extracellular hydrolysis of nucleotides to generate AMP and, in tandem with CD73, adenosine. We have recently found in addition that co-expression of CD39 and CD161 by human CD4⁺ T cells may become a biomarker of human Th17 cells. CD39 and CD161 have direct interactions that are further linked with acid sphingomyelinase (ASM). Upon activation of CD39 and CD161, the molecular interactions boost ASM bio-activity, which generates cellular ceramide to further mediate downstream signals inclusive of STAT3 and mTOR. We suggest modulation of human Th17 responsiveness by CD39 and CD161 and describe novel molecular mechanisms integrating elements of both extracellular nucleotide and sphingolipid homeostasis that are pivotal in the control of human Th17 cells and which could have therapeutic potential.