Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells.
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(+)CD25(high)FOXP3(+) Treg overexpress CD39 and CD73, ectonucleotidases sequentially converting ATP into AMP and adenosine, which then binds to A(2a) receptors on effector T cells, suppressing their functions. CD4(+)CD39(+) and CD4(+)CD25(high) 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. ARL67156) and antagonists of the A(2a) 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.
Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213-1863, USA.
Magis
M
Mandapathil
Benedict
B
Hilldorfer
Miroslaw J
MJ
Szczepanski
Malgorzata
M
Czystowska
Marta
M
Szajnik
Jin
J
Ren
Stephan
S
Lang
Edwin K
EK
Jackson
Elieser
E
Gorelik
Theresa L
TL
Whiteside
D015720:5'-Nucleotidase / Q000276:immunology; D000241:Adenosine / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001081:Apyrase / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D058851:GPI-Linked Proteins; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; C508017:IL2RA protein, human; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine