期刊
ONCOIMMUNOLOGY
卷 5, 期 2, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2015.1082703
关键词
Autocrine regulation; CD39 and CD73 expression; 5 '-AMP and adenosine production; regulatory B cells (Breg); T-cell suppression
资金
- NIH [R0-1 CA 1168628, NS087978, HL109002, DK091190, HL069846, DK068575, DK079307]
- PDSE/CAPES (Brazil)
- [P30 CA047904]
CD39 and CD73 are key enzymes in the adenosine (ADO) pathway. ADO modulates pathophysiological responses of immune cells, including B cells. It has recently emerged that a subpopulation of ADO-producing CD39(+)CD73(+) B cells has regulatory properties. Here, we define the CD39(high) subset of these cells as the major contributor to the regulatory network operated by human B lymphocytes. Peripheral blood B cells were sorted into CD39(neg), CD39(inter) and CD39(high) subsets. The phenotype, proliferation and IL-10 secretion by these B cells were studied by flow cytometry. 5'-AMP and ADO levels were measured by mass spectrometry. Agonists or antagonists of A(1)R, A(2)AR and A(3)R were used to study ADO-receptor signaling in B cells. Inhibition of effector T-cell (Teff) activation/proliferation by B cells was assessed in co-cultures. Cytokine production was measured by Luminex. Upon in vitro activation and culture of B cells, the subset of CD39(high) B cells increased in frequency (p < 0.001). CD39(high) B cells upregulated CD73 expression, proliferated (approximately 40% of CD39(high) B cells were Ki-67(+) and secreted fold-2 higher IL-10 and ADO levels than CD39(neg) or CD39(inter) B cells. CD39(high) B cells co-cultured with autologous Teff suppressed T-cell activation/proliferation and secreted elevated levels of IL-6 and IL-10. The A(1)R and A(2A)R agonists promoted expansion and functions of CD39(high) B cells. CD39 ectonucleotidase is upregulated in a subset of in vitro-activated B cells which utilize ADO and IL-10 to suppress Teff functions. Proliferation and functions of these CD39(high) B cells are regulated by A(1)R- and A(2A)R-mediated autocrine signaling.
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