Notch ligands potentiate IL-7-driven proliferation and survival of human thymocyte precursors.
Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivo purified CD34(+) triple negative (TN) surface (s) CD3(-) CD4(-)CD8(-) (CD3(-)CD4(-)CD8(-)), CD4 immature single positive (ISP) (sCD3(-)CD4(+)CD8(-)) and double positive (DP) (sCD3(-)CD4(+)CD8(+)) human thymic precursors to mature DP expressing sCD3 (sCD3(+)CD4(+)CD8(+)). We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34(+) TN and to a lesser extent of CD4(+) ISP precursors. This effect of Notch is related to a sustained induction of IL-7 receptor alpha chain expression on thymocytes through a decreased methylation of its gene promoter. Thus, we show here that proliferation and differentiation of T-cell precursors are differentially modulated by IL-7 depending on the presence or absence of external signals. These results may have important implications for the clinical use of this cytokine as a strategy aimed at improving immune restoration.
Inserm U 955, Université Paris XII, France.
Maymouna
M
Magri
Ahmad
A
Yatim
Clarisse
C
Benne
Michèle
M
Balbo
Adeline
A
Henry
Alain
A
Serraf
Seiji
S
Sakano
Louis
L
Gazzolo
Yves
Y
Lévy
Jean-Daniel
JD
Lelièvre
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34 / Q000276:immunology; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000276:immunology* / Q000494:pharmacology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C508605:IL7 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020395:Receptors, Interleukin-7; D051880:Receptors, Notch; C064045:delta protein