Human CD4+CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells

Schuler, Patrick J.; Saze, Zenichiro; Hong, Chang‐Sook; Müller, Laurent; Gillespie, Delbert G.; Cheng, Dongmei; Harasymczuk, Malgorzata; Mandapathil, Magis; Lang, Stephan; Jackson, Edwin K.; Whiteside, Theresa L.

doi:10.1111/cei.12354

Cited by 228 publications

(238 citation statements)

References 40 publications

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“…Adenosine is a wellknown immunosuppressive factor that signals to effector T cells (Teffs) via the adenosine A 2A receptor (A2AR) to upregulate cAMP levels and inhibit Teff function (53). TEX carry CD39 and CD73, the ectonucleotidases responsible for ATP-dependent adenosine production, thereby serving as vehicles for the delivery of these enzymes to target cells (54). CD39 + Tregs in the TME are beneficiaries of this process, as continuous TEX-mediated CD73 delivery enables them to increase adenosine production and upregulate immunosuppressive functions (55).…”

Section: Functional Attributes Of Texmentioning

confidence: 99%

Exosomes and tumor-mediated immune suppression

Whiteside¹

2016

Journal of Clinical Investigation

454

377

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Tumor-derived exosomes (TEX) are harbingers of tumor-induced immune suppression: they carry immunosuppressive molecules and factors known to interfere with immune cell functions. By delivering suppressive cargos consisting of proteins similar to those in parent tumor cells to immune cells, TEX directly or indirectly influence the development, maturation, and antitumor activities of immune cells. TEX also deliver genomic DNA, mRNA, and microRNAs to immune cells, thereby reprogramming functions of responder cells to promote tumor progression. TEX carrying tumor-associated antigens can interfere with antitumor immunotherapies. TEX also have the potential to serve as noninvasive biomarkers of tumor progression. In the tumor microenvironment, TEX may be involved in operating numerous signaling pathways responsible for the downregulation of antitumor immunity.

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Section: Functional Attributes Of Texmentioning

confidence: 99%

Exosomes and tumor-mediated immune suppression

Whiteside¹

2016

Journal of Clinical Investigation

454

377

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“…Cytometry revealed an increased number of CD8 + (T suppressor/cytotoxic) and CD19 + splenocytes seemed to play an important role. We intend, in the near future, to carry out a more detailed study of splenocytes, among others, to investigate the presence of markers characteristic for regulatory T and B cells (Saze et al 2013, Schuler et al 2014, Figueiro et al 2016. Hypertrophic changes in renal glomeruli might be connected with increased concentration of bFGF and VEGF in the sera of E group progeny.…”

Section: Discussionmentioning

confidence: 99%

Morphometric abnormalities in spleen and kidney of the progeny of mice fed American cranberry extract (Vaccinium macrocarpon) during pregnancy and lactation

Bałan¹,

Lewicki²,

Siwicki³

et al. 2017

Polish Journal of Veterinary Sciences

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Cranberries and cranberry-derived diet supplements are often recommended for the treatment of urinary tract infections, also during pregnancy. These products contain strongly anti-angiogenic chemical compounds which could not be indifferent to the developing fetus. In the present work we evaluated the effect of feeding pregnant and lactating mice American cranberry extract (daily dose 0.88 mg) on the morphology and some parameters of spleen and kidney function of their adult progeny. Six weeks after delivery the morphometry of spleen and kidney, cytometric analysis of spleen lymphocytes, evaluation of humoral response to SRBC (Sheep Red Blood Cells), and examination of serum creatinine/urea concentration, were performed in the offspring. Spleens of progeny from experimental (E) group differed from the spleens of progeny of control mice in the lower number of lymphatic nodules and their larger diameter. Cytometry of spleen cells from progeny of E mothers revealed more CD19 + and CD8 + lymphocytes than in the control group. No difference was seen in the response to immunization by red blood cells of sheep (SRBC) between control and E offspring. An increase in the diameter of glomeruli was observed in the kidneys of the experimental group in comparison with the control group. No abnormalities in creatinine and urea serum level were observed. A higher concentration of VEGF and bFGF in E offspring sera in comparison to the controls was seen. Conclusion: Although the observed differences between the control and experimental group were not large, caution is recommended in using cranberries and their extracts during pregnancy until more research will be done on this topic.

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“…Initially, CD39+/CD73+ microvesicles were discovered in different cancer cell types and were actually shown to be able to suppress T-cell function through adenosine production [106]. Contributing to this body of evidence, it was demonstrated that CD4+CD39+Tregs act in cooperation with CD73-expressing-exossomes or with other lymphocytes expressing CD73 to mediate ADO-driven immune suppression [107]. Taken together, these studies clearly build a complex scenario in which adenosine production is the final product of a range of possible dynamic processes that include Tregs, as well as cooperative arrangements between different cell types and membrane-bound vesicles.…”

Section: Regulatory T-cells and Adenosinementioning

confidence: 99%

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Purinergic Signalling

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Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. This nucleotide is produced, in part, by the action of the ectoenzymes CD39 and CD73. Interestingly, these proteins are expressed on the cell surface of regulatory T-cells (Tregs) and mesenchymal stromal cells (MSCs)-two cell populations that have emerged as potential therapeutic tools in the field of cell therapy. In fact, the production of adenosine constitutes a mechanism used by both cell types to control the immune response. Recently, great scientific progress was obtained regarding the role of adenosine in the inflammatory environment. In this context, the present review focuses on the advances related to the impact of adenosine production over the immune modulatory activity of Tregs and MSCs, and how this nucleotide controls the biological functions of these cells. Finally, we mention the main challenges and hurdles to bring such molecule to clinical settings.

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Human CD4+CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells

Abstract: Summary

Cited by 228 publications

References 40 publications

Exosomes and tumor-mediated immune suppression

Exosomes and tumor-mediated immune suppression

Morphometric abnormalities in spleen and kidney of the progeny of mice fed American cranberry extract (Vaccinium macrocarpon) during pregnancy and lactation

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

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