Notch ligands potentiate IL-7-driven proliferation and survival of human thymocyte precursors

被引:30
作者
Magri, Maymouna
Yatim, Ahmad
Benne, Clarisse
Balbo, Michele
Henry, Adeline
Serraf, Alain [2 ]
Sakano, Seiji [3 ]
Gazzolo, Louis [4 ]
Levy, Yves [5 ]
Lelievre, Jean-Daniel [1 ,5 ]
机构
[1] Univ Paris 12, U955, Fac Med, INSERM, F-94010 Creteil, France
[2] Ctr Chirurg Marie Lannelongue, Le Plessis Robinson, France
[3] Asahi Kasei Corp, Corp Res & Dev, Shizuoka, Japan
[4] Ecole Normale Super Lyon, Virol Humaine INSERM, U758, Lyon, France
[5] CHU Henri Mondor, Serv Immunol Clin, F-94010 Creteil, France
关键词
Delta; 1; 4; IL-7; receptor; Notch; T-CELL DEVELOPMENT; THYMUS ORGAN-CULTURE; HUMAN BONE-MARROW; CORD BLOOD-CELLS; PROGENITOR CELLS; DIFFERENTIATION; RECEPTOR; EXPRESSION; IL-7; LINEAGE;
D O I
10.1002/eji.200838765
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1231 / 1240
页数:10
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