Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes.
The interaction of integrin αE(CD103)β7, often expressed on tumor-infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E-cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-β1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8(+)/CD103(-) T cell clone specific of a lung tumor-associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-β1 can participate in CD103 expression on locally TCR-engaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction.
INSERM U753, F-94805 Villejuif, France;
M'barka
M
Mokrani
Jihène
J
Klibi
Dominique
D
Bluteau
Georges
G
Bismuth
Fathia
F
Mami-Chouaib
D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051899:Smad2 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D039001:Integrin alpha Chains; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011948:Receptors, Antigen, T-Cell; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C091367:alpha E integrins