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

Abstract

Summary 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 αCD3/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 αCD3/CD28‐stimulated CD8 cells. Consequently, αCD3/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.

Autoimmunity in CD73/Ecto-5′-Nucleotidase Deficient Mice Induces Renal Injury

“…It is also known that adenosine prevents the priming of naïve CD8 cytotoxic T cells [26] by antigen-presenting cells. In our study, IgG deposition in the glomeruli was associated with the presence of CD25+activated CD8+T cells.…”

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…27,28 Adenosine, which is present at increased concentrations in cancer tissue, 29,30 has a crucial role in the activity alteration of immune cells including Tregs 31 and CD8 C T cells. 32 We found that a large fraction of CD39 C gdT cells co-expressed CD73 (Fig. 4A).…”

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

“…47,48 Additionally, stimulation of A 2A adenosine receptors suppresses the production of interferon-γ (IFN-γ) and IL-4 by both naive CD4 + T cells and polarized type 1 T helper (T H ) cells and T H 2 cells. 11,47,49,50 Similarly, adenosine suppresses the activity of naive CD8 + T cells 51 and controls the effector functions of fully differentiated CD8 + T cells. 49,52,53 However, the role of adenosine in regulating T cell functions at onset of T1DM is incompletely understood.…”