Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo.
To evaluate the direct effect of adenosine on cytokine-polarized effector T cells, murine type 1 helper T cells (Th1) and type 1 cytotoxic T lymphocytes (Tc1) and Th2/Tc2 cells were generated using an antigen-presenting cell (APC)-free method. Tc1 and Tc2 cells had similar adenosine signaling, as measured by intracellular cyclic AMP (cAMP) increase upon adenosine A(2A) receptor agonism by CGS21680 (CGS). CGS greatly reduced Tc1 and Tc2 cell interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) secretion, with nominal effect on interferon gamma (IFN-gamma) secretion. Tc2 cell IL-4 and IL-5 secretion was not reduced by CGS, and IL-10 secretion was moderately reduced. Agonist-mediated inhibition of IL-2 and TNF-alpha secretion occurred via A(2A) receptors, with no involvement of A(1), A(2B), or A(3) receptors. Adenosine agonist concentrations that abrogated cytokine secretion did not inhibit Tc1 or Tc2 cell cytolytic function. Adenosine modulated effector T cells in vivo, as CGS administration reduced CD4(+)Th1 and CD8(+)Tc1 cell expansion to alloantigen and, in a separate model, reduced antigen-specific CD4(+) Th1 cell numbers. Remarkably, agonist-mediated T-cell inhibition was abrogated by in vivo IL-2 therapy. Adenosine receptor activation therefore preferentially inhibits type I cytokine secretion, most notably IL-2. Modulation of adenosine receptors may thus represent a suitable target primarily for inflammatory conditions mediated by Th1 and Tc1 cells.
Erdmann
Andreas A
AA
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm 12N226, Bethesda, MD 20892, USA.
Gao
Zhan-Guo
ZG
Jung
Unsu
U
Foley
Jason
J
Borenstein
Todd
T
Jacobson
Kenneth A
KA
Fowler
Daniel H
DH
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010627:Phenethylamines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D016753:Interleukin-10; D007371:Interferon-gamma; D000242:Cyclic AMP; D000241:Adenosine
Methods Mol Biol. 2000;126:363-74
10685423
J Exp Med. 1999 Oct 4;190(7):995-1004
10510089
Annu Rev Pharmacol Toxicol. 2001;41:775-87
11264476
J Exp Med. 2001 Nov 19;194(10):F53-7
11714761
Pharmacol Rev. 2001 Dec;53(4):527-52
11734617
Am J Physiol Renal Physiol. 2002 Jan;282(1):F10-8
11739107
Nature. 2001 Dec 20-27;414(6866):916-20
11780065
Annu Rev Immunol. 2002;20:323-70
11861606
J Clin Invest. 2002 Aug;110(4):463-74
12189240
J Exp Med. 2002 Oct 7;196(7):999-1005
12370261
J Clin Oncol. 2003 Aug 15;21(16):3127-32
12915604
Blood. 2003 Nov 1;102(9):3439-46
12855580
J Immunol. 1981 Jun;126(6):2457-60
7014718
J Exp Med. 1987 Dec 1;166(6):1894-9
3500267
Nature. 1987 Dec 17-23;330(6149):662-4
3317066
J Pharmacol Exp Ther. 1989 Dec;251(3):888-93
2600819
J Exp Med. 1990 Sep 1;172(3):921-9
2117636
Anal Biochem. 1990 Sep;189(2):231-4
2177960
Mol Pharmacol. 1992 Feb;41(2):352-9
1311411
Eur J Immunol. 1993 Apr;23(4):790-5
8384558
Int Immunol. 1993 Jun;5(6):565-72
8102248
J Immunol. 1994 Feb 1;152(3):1004-13
7905495
Cancer Res. 1994 Jul 1;54(13):3521-6
8012976
J Immunol. 1995 Jul 15;155(2):585-93
7608537
Int Immunol. 1995 Jun;7(6):891-904
7577797
J Immunol. 1996 Oct 1;157(7):2909-15
8816396
Curr Opin Immunol. 1996 Jun;8(3):336-42
8793995
J Immunol. 1996 Nov 15;157(10):4634-40
8906843
Blood. 1997 Aug 15;90(4):1600-10
9269779
J Biol Chem. 1997 Oct 10;272(41):25881-9
9325320
J Clin Invest. 1999 Sep;104(6):777-85
10491413
Br J Pharmacol. 2000 Sep;131(1):43-50
10960067