Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells.
Extracellular adenosine and purine nucleotides are elevated in many pathological situations associated with the expansion of CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs). Therefore, we tested whether adenosinergic pathways play a role in MDSC expansion and functions. We found that A(2B) adenosine receptors on hematopoietic cells play an important role in accumulation of intratumoral CD11b(+)Gr1(high) cells in a mouse Lewis lung carcinoma model in vivo and demonstrated that these receptors promote preferential expansion of the granulocytic CD11b(+)Gr1(high) subset of MDSCs in vitro. Flow cytometry analysis of MDSCs generated from mouse hematopoietic progenitor cells revealed that the CD11b(+)Gr-1(high) subset had the highest levels of CD73 (ecto-5'-nucleotidase) expression (Δmean fluorescence intensity [MFI] of 118.5 ± 16.8), followed by CD11b(+)Gr-1(int) (ΔMFI of 57.9 ± 6.8) and CD11b(+)Gr-1(-/low) (ΔMFI of 12.4 ± 1.0) subsets. Even lower levels of CD73 expression were found on Lewis lung carcinoma tumor cells (ΔMFI of 3.2 ± 0.2). The high levels of CD73 expression in granulocytic CD11b(+)Gr-1(high) cells correlated with high levels of ecto-5'-nucleotidase enzymatic activity. We further demonstrated that the ability of granulocytic MDSCs to suppress CD3/CD28-induced T cell proliferation was significantly facilitated in the presence of the ecto-5'-nucleotidase substrate 5'-AMP. We propose that generation of adenosine by CD73 expressed at high levels on granulocytic MDSCs may promote their expansion and facilitate their immunosuppressive activity.
Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN 37232-6300, USA.
Sergey
S
Ryzhov
Sergey V
SV
Novitskiy
Anna E
AE
Goldstein
Asel
A
Biktasova
Michael R
MR
Blackburn
Italo
I
Biaggioni
Mikhail M
MM
Dikov
Igor
I
Feoktistov
D015720:5'-Nucleotidase / Q000276:immunology / Q000378:metabolism; D000241:Adenosine / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D018827:Carcinoma, Lewis Lung; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018047:Receptors, Purinergic P1 / Q000276:immunology / Q000378:metabolism
D039481:CD11b Antigen; D018047:Receptors, Purinergic P1; D015720:5'-Nucleotidase; D000241:Adenosine