Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling

Linnemann C, Schildberg FA, Schurich A, Diehl L, Hegenbarth SI, Endl E, Lacher S, Mueller CE, Frey J, Simeoni L, Schraven B, et al. (2009)
IMMUNOLOGY 128(1pt2): e728-e737.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Linnemann, Carsten; Schildberg, Frank A.; Schurich, Anna; Diehl, Linda; Hegenbarth, Silke I.; Endl, Elmar; Lacher, Svenja; Mueller, Christa E.; Frey, JürgenUniBi; Simeoni, Luca; Schraven, Burkhart; Stabenow, Dirk
Abstract / Bemerkung
P>Adenosine is a well-described anti-inflammatory modulator of immune responses within peripheral tissues. Extracellular adenosine accumulates in inflamed and damaged tissues and inhibits the effector functions of various immune cell populations, including CD8 T cells. However, it remains unclear whether extracellular adenosine also regulates the initial activation of naive CD8 T cells by professional and semi-professional antigen-presenting cells, which determines their differentiation into effector or tolerant CD8 T cells, respectively. We show that adenosine inhibited the initial activation of murine naive CD8 T cells after alpha CD3/CD28-mediated stimulation. Adenosine caused inhibition of activation, cytokine production, metabolic activity, proliferation and ultimately effector differentiation of naive CD8 T cells. Remarkably, adenosine interfered efficiently with CD8 T-cell priming by professional antigen-presenting cells (dendritic cells) and semi-professional antigen-presenting cells (liver sinusoidal endothelial cells). Further analysis of the underlying mechanisms demonstrated that adenosine prevented rapid tyrosine phosphorylation of the key kinase ZAP-70 as well as Akt and ERK1/2 in naive alpha CD3/CD28-stimulated CD8 cells. Consequently, alpha CD3/CD28-induced calcium-influx into CD8 cells was reduced by exposure to adenosine. Our results support the notion that extracellular adenosine controls membrane-proximal T-cell receptor signalling and thereby also differentiation of naive CD8 T cells. These data raise the possibility that extracellular adenosine has a physiological role in the regulation of CD8 T-cell priming and differentiation in peripheral organs.
cell activation; T cells; T-cell receptor; signal transduction
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Linnemann C, Schildberg FA, Schurich A, et al. Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. IMMUNOLOGY. 2009;128(1pt2):e728-e737.
Linnemann, C., Schildberg, F. A., Schurich, A., Diehl, L., Hegenbarth, S. I., Endl, E., Lacher, S., et al. (2009). Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. IMMUNOLOGY, 128(1pt2), e728-e737.
Linnemann, Carsten, Schildberg, Frank A., Schurich, Anna, Diehl, Linda, Hegenbarth, Silke I., Endl, Elmar, Lacher, Svenja, et al. 2009. “Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling”. IMMUNOLOGY 128 (1pt2): e728-e737.
Linnemann, C., Schildberg, F. A., Schurich, A., Diehl, L., Hegenbarth, S. I., Endl, E., Lacher, S., Mueller, C. E., Frey, J., Simeoni, L., et al. (2009). Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. IMMUNOLOGY 128, e728-e737.
Linnemann, C., et al., 2009. Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. IMMUNOLOGY, 128(1pt2), p e728-e737.
C. Linnemann, et al., “Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling”, IMMUNOLOGY, vol. 128, 2009, pp. e728-e737.
Linnemann, C., Schildberg, F.A., Schurich, A., Diehl, L., Hegenbarth, S.I., Endl, E., Lacher, S., Mueller, C.E., Frey, J., Simeoni, L., Schraven, B., Stabenow, D., Knolle, P.A.: Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. IMMUNOLOGY. 128, e728-e737 (2009).
Linnemann, Carsten, Schildberg, Frank A., Schurich, Anna, Diehl, Linda, Hegenbarth, Silke I., Endl, Elmar, Lacher, Svenja, Mueller, Christa E., Frey, Jürgen, Simeoni, Luca, Schraven, Burkhart, Stabenow, Dirk, and Knolle, Percy A. “Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling”. IMMUNOLOGY 128.1pt2 (2009): e728-e737.

23 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells.
Sorrentino C, Hossain F, Rodriguez PC, Sierra RA, Pannuti A, Osborne BA, Minter LM, Miele L, Morello S., Front Immunol 10(), 2019
PMID: 30792717
Myeloid-Derived Suppressor Cells: Ductile Targets in Disease.
Consonni FM, Porta C, Marino A, Pandolfo C, Mola S, Bleve A, Sica A., Front Immunol 10(), 2019
PMID: 31130949
Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function.
Vigano S, Alatzoglou D, Irving M, Ménétrier-Caux C, Caux C, Romero P, Coukos G., Front Immunol 10(), 2019
PMID: 31244820
Targeting adenosine for cancer immunotherapy.
Leone RD, Emens LA., J Immunother Cancer 6(1), 2018
PMID: 29914571
Targeting Adenosine Receptor Signaling in Cancer Immunotherapy.
Sek K, Mølck C, Stewart GD, Kats L, Darcy PK, Beavis PA., Int J Mol Sci 19(12), 2018
PMID: 30513816
Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer.
Hu G, Wu P, Cheng P, Zhang Z, Wang Z, Yu X, Shao X, Wu D, Ye J, Zhang T, Wang X, Qiu F, Yan J, Huang J., Oncoimmunology 6(2), 2017
PMID: 28344891
Purinergic regulation of the immune system.
Cekic C, Linden J., Nat Rev Immunol 16(3), 2016
PMID: 26922909
Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer.
Riese MJ, Moon EK, Johnson BD, Albelda SM., Front Cell Dev Biol 4(), 2016
PMID: 27800476
Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations.
Antonioli L, Blandizzi C, Csóka B, Pacher P, Haskó G., Nat Rev Endocrinol 11(4), 2015
PMID: 25687993
CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression.
Bono MR, Fernández D, Flores-Santibáñez F, Rosemblatt M, Sauma D., FEBS Lett 589(22), 2015
PMID: 26226423
T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1.
Trad M, Gautheron A, Fraszczak J, Alizadeh D, Larmonier C, LaCasse CJ, Centuori S, Audia S, Samson M, Ciudad M, Bonnefoy F, Lemaire-Ewing S, Katsanis E, Perruche S, Saas P, Bonnotte B., Biomed Res Int 2015(), 2015
PMID: 26491691
NADH oxidase-dependent CD39 expression by CD8(+) T cells modulates interferon gamma responses via generation of adenosine.
Bai A, Moss A, Rothweiler S, Serena Longhi M, Wu Y, Junger WG, Robson SC., Nat Commun 6(), 2015
PMID: 26549640
Targeting CD73 and downstream adenosine receptor signaling in triple-negative breast cancer.
Allard B, Turcotte M, Stagg J., Expert Opin Ther Targets 18(8), 2014
PMID: 24798880
Extracellular adenosine-mediated modulation of regulatory T cells.
Ohta A, Sitkovsky M., Front Immunol 5(), 2014
PMID: 25071765
Autoimmunity in CD73/Ecto-5'-nucleotidase deficient mice induces renal injury.
Blume C, Felix A, Shushakova N, Gueler F, Falk CS, Haller H, Schrader J., PLoS One 7(5), 2012
PMID: 22666342
Regulation of lymphocyte function by adenosine.
Linden J, Cekic C., Arterioscler Thromb Vasc Biol 32(9), 2012
PMID: 22772752
Immunological alterations mediated by adenosine during host-microbial interactions.
Drygiannakis I, Ernst PB, Lowe D, Glomski IJ., Immunol Res 50(1), 2011
PMID: 21479929

50 References

Daten bereitgestellt von Europe PubMed Central.

Characterization of adenosine deaminase binding to human CD26 on T cells and its biologic role in immune response.
Dong RP, Kameoka J, Hegen M, Tanaka T, Xu Y, Schlossman SF, Morimoto C., J. Immunol. 156(4), 1996
PMID: 8568233
Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC., J. Exp. Med. 204(6), 2007
PMID: 17502665
Resolvins and protectins in the termination program of acute inflammation.
Ariel A, Serhan CN., Trends Immunol. 28(4), 2007
PMID: 17337246
Purine and pyrimidine receptors.
Burnstock G., Cell. Mol. Life Sci. 64(12), 2007
PMID: 17375261
Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells.
Koshiba M, Kojima H, Huang S, Apasov S, Sitkovsky MV., J. Biol. Chem. 272(41), 1997
PMID: 9325320
Apoptosis induced by modified ribonucleosides in human cell culture systems.
Meisel H, Gunther S, Martin D, Schlimme E., FEBS Lett. 433(3), 1998
PMID: 9744808
Inducible cyclooxygenase may have anti-inflammatory properties.
Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA., Nat. Med. 5(6), 1999
PMID: 10371510
A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells.
Lappas CM, Rieger JM, Linden J., J. Immunol. 174(2), 2005
PMID: 15634932
Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4.
Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M., Nat. Immunol. 6(3), 2005
PMID: 15685176
The 'danger' sensors that STOP the immune response: the A2 adenosine receptors?
Sitkovsky MV, Ohta A., Trends Immunol. 26(6), 2005
PMID: 15922945
Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo.
Erdmann AA, Gao ZG, Jung U, Foley J, Borenstein T, Jacobson KA, Fowler DH., Blood 105(12), 2005
PMID: 15746085
Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway.
Cose S, Brammer C, Khanna KM, Masopust D, Lefrancois L., Eur. J. Immunol. 36(6), 2006
PMID: 16708400
Cutting edge: Critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis.
Naganuma M, Wiznerowicz EB, Lappas CM, Linden J, Worthington MT, Ernst PB., J. Immunol. 177(5), 2006
PMID: 16920910
A2A adenosine receptor protects tumors from antitumor T cells.
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, Chen JF, Jackson EK, Apasov S, Abrams S, Sitkovsky M., Proc. Natl. Acad. Sci. U.S.A. 103(35), 2006
PMID: 16916931
Steady-state and inflammatory dendritic-cell development.
Shortman K, Naik SH., Nat. Rev. Immunol. 7(1), 2006
PMID: 17170756
Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition.
Sevigny CP, Li L, Awad AS, Huang L, McDuffie M, Linden J, Lobo PI, Okusa MD., J. Immunol. 178(7), 2007
PMID: 17371980
A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.
Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, Drake CG, Powell JD., Blood 111(1), 2007
PMID: 17909080
Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance.
Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA., Hepatology 47(1), 2008
PMID: 17975811
CD8+ T cell effector mechanisms in resistance to infection.
Harty JT, Tvinnereim AR, White DW., Annu. Rev. Immunol. 18(), 2000
PMID: 10837060
Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.
Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, Momburg F, Arnold B, Knolle PA., Nat. Med. 6(12), 2000
PMID: 11100119
Complex regulation of nucleoside transporter expression in epithelial and immune system cells.
Pastor-Anglada M, Casado FJ, Valdes R, Mata J, Garcia-Manteiga J, Molina M., Mol. Membr. Biol. 18(1), 2001
PMID: 11396615
International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors.
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J., Pharmacol. Rev. 53(4), 2001
PMID: 11734617
Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells.
Hoskin DW, Butler JJ, Drapeau D, Haeryfar SM, Blay J., Int. J. Cancer 99(3), 2002
PMID: 11992407
The CD28 signaling pathway regulates glucose metabolism.
Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB., Immunity 16(6), 2002
PMID: 12121659
Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.
Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP., J. Clin. Invest. 110(7), 2002
PMID: 12370277
Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation.
Pouliot M, Fiset ME, Masse M, Naccache PH, Borgeat P., J. Immunol. 169(9), 2002
PMID: 12391247
Bone marrow as a priming site for T-cell responses to blood-borne antigen.
Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hammerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V., Nat. Med. 9(9), 2003
PMID: 12910264
Adenosine: an endogenous regulator of innate immunity.
Hasko G, Cronstein BN., Trends Immunol. 25(1), 2004
PMID: 14698282
Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors.
Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M., Annu. Rev. Immunol. 22(), 2004
PMID: 15032592
The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.
Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P., J. Clin. Invest. 114(5), 2004
PMID: 15343389
Brain adenosine concentration during hypoxia in rats.
Winn HR, Rubio R, Berne RM., Am. J. Physiol. 241(2), 1981
PMID: 6791511
Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre.
Zetterstrom T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB., Neurosci. Lett. 29(2), 1982
PMID: 7088412
The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity.
Bergman M, Mustelin T, Oetken C, Partanen J, Flint NA, Amrein KE, Autero M, Burn P, Alitalo K., EMBO J. 11(8), 1992
PMID: 1639064
Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate.
Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW., Science 262(5136), 1993
PMID: 7694366
Location of cAMP-dependent protein kinase type I with the TCR-CD3 complex.
Skalhegg BS, Tasken K, Hansson V, Huitfeldt HS, Jahnsen T, Lea T., Science 263(5143), 1994
PMID: 8272870
Mechanism of inhibition of Raf-1 by protein kinase A.
Hafner S, Adler HS, Mischak H, Janosch P, Heidecker G, Wolfman A, Pippig S, Lohse M, Ueffing M, Kolch W., Mol. Cell. Biol. 14(10), 1994
PMID: 7935389
Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release.
Decking UK, Schlieper G, Kroll K, Schrader J., Circ. Res. 81(2), 1997
PMID: 9242176
cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes.
Bodor J, Spetz AL, Strominger JL, Habener JF., Proc. Natl. Acad. Sci. U.S.A. 93(8), 1996
PMID: 8622971

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