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.
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Felipe
F
Flores-Santibáñez
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Dominique
D
Fernández
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Daniel
D
Meza
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Gabriela
G
Tejón
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Leonardo
L
Vargas
Centro de Investigaciones Biomedicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
Lorena
L
Varela-Nallar
Centro de Investigaciones Biomedicas, Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
Sebastián
S
Arredondo
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Victoria
V
Guixé
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.|Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile.|Fundacion Ciencia & Vida, Santiago, Chile.
Mario
M
Rosemblatt
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
María Rosa
MR
Bono
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Daniela
D
Sauma
D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000096:biosynthesis*; D000249:Adenosine Monophosphate / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D007156:Immunologic Memory; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D000249:Adenosine Monophosphate; D015720:5'-Nucleotidase; D000241:Adenosine
CD73; Tc17; adenosine; cell differentiation; stem cell; tumour immunology