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

Abstract

SummaryThe 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-b (TGF-b), and hence CD73 expression is related to the acquisition of immunosuppressive potential by these cells. TGF-b 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-c 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 instrating 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.

CD73 expression identifies a subset of IgM+ antigen‐experienced cells with memory attributes that is T cell and CD40 signalling dependent

“…CD73 signalling by adenosine through the adenosine receptor A 2A has been shown to support the survival of naive T cells responding to tonic signalling by preventing the downregulation of interleukin-7 receptor 57 and also to arrest the terminal differentiation of CD8 T cells. 58 Our data indicate that constitutive CD40 signalling may be involved in T-cell homeostasis. We also found that Peyer's patches of CD40 À/À mice had fewer Tfh cells and our results are in keeping with reports indicating that B-cell-T-cell interactions involving CD40 signalling promote Tfh cell differentiation.…”

“…However, frequencies were similar in μ MT mice, indicating that CD73 expression on T cells can be maintained by interactions with other CD40‐expressing cells in vivo . CD73 signalling by adenosine through the adenosine receptor A 2A has been shown to support the survival of naive T cells responding to tonic signalling by preventing the down‐regulation of interleukin‐7 receptor and also to arrest the terminal differentiation of CD8 T cells . Our data indicate that constitutive CD40 signalling may be involved in T‐cell homeostasis.…”

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets

“…Upon activation, CD8 + T cells commonly downregulate CD73 expression, although this is not a universal phenomenon . In human solid tumors, CD73 is expressed at high levels on memory CD8 + T cells and is absent or low on terminally differentiated effector CD8 + T cells . It was proposed that CD73‐derived adenosine and A2a regulate the transition from naive/memory CD8 + T cells to effector cells by inhibition of Wnt‐signaling shutdown …”

“…Th17 cells generated in the presence of IL‐23, TGF‐β3, and IL‐1β do not express CD73 and CD39 . Extracellular adenosine also acts in an autocrine fashion to stabilize Th17 cell differentiation by favoring the expression of stem cell‐related transcription factors such as tcf‐7 and lef‐1 and by restraining the acquisition of Th1 effector molecules such as granzyme B and IFNγ . Besides, activation of A2b receptors on DCs was shown to promote differentiation of IL‐17 producing T cells and their expression of IL‐23R and RORγt …”

“…62 In human solid tumors,CD73isexpressedathighlevelsonmemoryCD8 + T cells and isabsentor low on terminally differentiated effectorCD8 + T cells. 78 It was proposed that CD73-derived adenosine and A2a regulate the transitionfromnaive/memoryCD8 + Tcellstoeffectorcellsbyinhibi-tionofWnt-signalingshutdown. 78 Increased levels of CD39 + Foxp3 + Tregs are also found in human follicular lymphoma and linked to anergy of effector T cells due to high levels of adenosine.…”