CD73-mediated adenosine production promotes stem cell-like properties in mouse Tc17 cells

The CD73 ectonucleotidase catalyses the hydrolysis of AMP to adenosine, an immunosuppressive molecule. Recent evidence has demonstrated that this ectonucleotidase is up-regulated in T helper type 17 cells when generated in the presence of transforming growth factor-β (TGF-β), and hence CD73 expression is related to the acquisition of immunosuppressive potential by these cells. TGF-β is also able to induce CD73 expression in CD8⁺ T cells but the function of this ectonucleotidase in CD8⁺ T cells is still unknown. Here, we show that Tc17 cells present high levels of the CD73 ectonucleotidase and produce adenosine however, they do not suppress the proliferation of CD4⁺ T cells. Interestingly, we report that adenosine signalling through A2A receptor favours interleukin-17 production and the expression of stem cell-associated transcription factors such as tcf-7 and lef-1 but restrains the acquisition of Tc1-related effector molecules such as interferon-γ and Granzyme B by Tc17 cells. Within the tumour microenvironment, CD73 is highly expressed in CD62L⁺ CD127⁺ CD8⁺ T cells (memory T cells) and is down-regulated in GZMB⁺ KLRG1⁺ CD8⁺ T cells (terminally differentiated T cells), demonstrating that CD73 is expressed in memory/naive cells and is down-regulated during differentiation. These data reveal a novel function of CD73 ectonucleotidase in arresting CD8⁺ T-cell differentiation and support the idea that CD73-driven adenosine production by Tc17 cells may promote stem cell-like properties in Tc17 cells.