Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling.
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 naïve 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 naïve CD8 T cells after alphaCD3/CD28-mediated stimulation. Adenosine caused inhibition of activation, cytokine production, metabolic activity, proliferation and ultimately effector differentiation of naïve 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 naïve alphaCD3/CD28-stimulated CD8 cells. Consequently, alphaCD3/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 naïve 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.
Linnemann
Carsten
C
Institute for Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-University Bonn, Bonn, Germany.
Schildberg
Frank A
FA
Schurich
Anna
A
Diehl
Linda
L
Hegenbarth
Silke I
SI
Endl
Elmar
E
Lacher
Svenja
S
Müller
Christa E
CE
Frey
Jürgen
J
Simeoni
Luca
L
Schraven
Burkhart
B
Stabenow
Dirk
D
Knolle
Percy A
PA
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018106:CD28 Antigens; D017252:CD3 Complex; D007155:Immunologic Factors; D011948:Receptors, Antigen, T-Cell; D011494:Protein Kinases; D000241:Adenosine; D002118:Calcium