Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells(TREG). Export

@article{citeulike:6111178, abstract = {Naturally-occurring regulatory T cells (nTreg) are crucial for maintaining tolerance to self and thus preventing autoimmune diseases and allograft rejections. In cancer, Treg down-regulate antitumor responses by several distinct mechanisms. This study analyzes the role the adenosinergic pathway plays in suppressive activities of human nTreg. Human CD4+CD25highFOXP3+ Treg overexpress CD39 and CD73, ectonucleotidases sequentially converting ATP into AMP and adenosine, which then binds to A2a receptors on effector T cells, suppressing their functions. CD4+CD39+ and CD4+CD25high T cells express low levels of adenosine deaminase (ADA), the enzyme responsible for adenosine breakdown, and of CD26, a surface-bound glycoprotein associated with ADA. In contrast, T effector cells are enriched in CD26/ADA but express low levels of CD39 and CD73. Inhibitors of ectonucleotidase activity (e.g., ARL6756) and antagonists of the A2a receptor (e.g., ZM241385) blocked Treg-mediated immunosuppression. The inhibition of ADA activity on effector T cells enhanced Treg-mediated immunosuppression. Thus, human nTreg characterized by the presence of CD39 and the low expression of CD26/ADA are responsible for the generation of adenosine which plays a major role in Treg-mediated immunosuppression. The data suggest that the adenosinergic pathway represents a potential therapeutic target for regulation of immunosuppression in a broad variety of human diseases.}, author = {Mandapathil, Magis and Hilldorfer, Benedict and Szczepanski, Miroslaw J. and Czystowska, Malgorzata and Szajnik, Marta and Ren, Jin and Lang, Stephan and Jackson, Edwin K. and Gorelik, Elieser and Whiteside, Theresa L.}, citeulike-article-id = {6111178}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M109.047423}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19858205}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19858205}, day = {26}, doi = {10.1074/jbc.M109.047423}, issn = {1083-351X}, journal = {The Journal of biological chemistry}, keywords = {adenosine, treg, treg\_mechanism}, month = {October}, posted-at = {2009-11-13 22:44:53}, priority = {2}, title = {Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells(TREG).}, url = {http://dx.doi.org/10.1074/jbc.M109.047423}, year = {2009} }

TY - JOUR ID - citeulike:6111178 L3 - citeulike-article-id:6111178 N2 - Naturally-occurring regulatory T cells (nTreg) are crucial for maintaining tolerance to self and thus preventing autoimmune diseases and allograft rejections. In cancer, Treg down-regulate antitumor responses by several distinct mechanisms. This study analyzes the role the adenosinergic pathway plays in suppressive activities of human nTreg. Human CD4+CD25highFOXP3+ Treg overexpress CD39 and CD73, ectonucleotidases sequentially converting ATP into AMP and adenosine, which then binds to A2a receptors on effector T cells, suppressing their functions. CD4+CD39+ and CD4+CD25high T cells express low levels of adenosine deaminase (ADA), the enzyme responsible for adenosine breakdown, and of CD26, a surface-bound glycoprotein associated with ADA. In contrast, T effector cells are enriched in CD26/ADA but express low levels of CD39 and CD73. Inhibitors of ectonucleotidase activity (e.g., ARL6756) and antagonists of the A2a receptor (e.g., ZM241385) blocked Treg-mediated immunosuppression. The inhibition of ADA activity on effector T cells enhanced Treg-mediated immunosuppression. Thus, human nTreg characterized by the presence of CD39 and the low expression of CD26/ADA are responsible for the generation of adenosine which plays a major role in Treg-mediated immunosuppression. The data suggest that the adenosinergic pathway represents a potential therapeutic target for regulation of immunosuppression in a broad variety of human diseases. JF - The Journal of biological chemistry SN - 1083-351X TI - Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells(TREG). KW - adenosine KW - treg KW - treg_mechanism AU - Mandapathil, Magis AU - Hilldorfer, Benedict AU - Szczepanski, Miroslaw AU - Czystowska, Malgorzata AU - Szajnik, Marta AU - Ren, Jin AU - Lang, Stephan AU - Jackson, Edwin AU - Gorelik, Elieser AU - Whiteside, Theresa PY - 2009/10/26/ UR - http://dx.doi.org/10.1074/jbc.M109.047423 ER -