A novel mechanism of B cell-mediated immune suppression through CD73 expression and adenosine production.
Immune suppression by regulatory T cells and regulatory B cells is a critical mechanism to limit excess inflammation and autoimmunity. IL-10 is considered the major mediator of B cell-induced immune suppression. We report a novel mechanism for immune suppression through adenosine generation by B cells. We identified a novel population of B cells that expresses CD73 as well as CD39, two ectoenzymes that together catalyze the extracellular dephosphorylation of adenine nucleotides to adenosine. Whereas CD39 expression is common among B cells, CD73 expression is not. Approximately 30-50% of B-1 cells (B220(+)CD23(-)) and IL-10-producing B (B10) cells (B220(+)CD5(+)CD1d(hi)) are CD73(hi), depending on mouse strain, whereas few conventional B-2 cells (B220(+)CD23(+)AA4.1(-)) express CD73. In keeping with expression of both CD73 and CD39, we found that CD73(+) B cells produce adenosine in the presence of substrate, whereas B-2 cells do not. CD73(-/-) mice were more susceptible to dextran sulfate sodium salt (DSS)-induced colitis than wild type (WT) mice were, and transfer of CD73(+) B cells ameliorated the severity of colitis, suggesting that B cell CD73/CD39/adenosine can modulate DSS-induced colitis. IL-10 production by B cells is not affected by CD73 deficiency. Interestingly, adenosine generation by IL-10(-/-) B cells is impaired because of reduced expression of CD73, indicating an unexpected connection between IL-10 and adenosine and suggesting caution in interpreting the results of studies with IL-10(-/-) cells. Our findings demonstrate a novel regulatory role of B cells on colitis through adenosine generation in an IL-10-independent manner.
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030; and hkaku@nshs.edu.
Hiroaki
H
Kaku
Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
Kai Fan
KF
Cheng
Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY 11030.
Yousef
Y
Al-Abed
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030; and.
Thomas L
TL
Rothstein
D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000096:biosynthesis*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001081:Apyrase / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D056747:Immunomodulation / Q000235:genetics; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010529:Peritoneal Cavity / Q000166:cytology; D010641:Phenotype
D015703:Antigens, CD; D016753:Interleukin-10; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine