Tumor necrosis factor-α and CD80 modulate CD28 expression through a similar mechanism of T-cell receptor-independent inhibition of transcription

被引:35
作者
Lewis, DE
Merched-Sauvage, M
Goronzy, JJ
Weyand, CM
Vallejo, AN
机构
[1] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA
[2] Emory Univ, Sch Med, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA
[3] Mayo Clin, Dept Med, Div Rheumatol, Rochester, MN 55905 USA
关键词
D O I
10.1074/jbc.M402194200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Replicative senescence of human T cells is characterized by the loss of CD28 expression, exemplified by the clonal expansion of CD28(null) T cells during repeated stimulation in vitro as well as in chronic inflammatory and infectious diseases and in the normal course of aging. Because CD28 is the major costimulatory receptor for the induction of T cell-mediated immunity, the mechanism(s) underlying CD28 loss is of paramount interest. Current models of replicative senescence involve protracted procedures to generate CD28(null) cells from CD28(+) precursors; hence, a T-cell line model was used to examine the dynamics of CD28 expression. Here, we show the versatility of the JT and Jtag cell lines in tracking CD28(null) <----> CD28(hi) phenotypic transitions. JT and Jtag cells were CD28(null) and CD28(lo), respectively, but expressed high levels of CD28 when exposed to phorbol 12-myristate 13-acetate. This was a result of the reconstitution of the CD28 gene transcriptional initiator (INR). Tumor necrosis factor-alpha reduced CD28 expression because of the inhibition of INR-driven transcription. Ligation of CD28 by an antibody or by CD80 also down-regulated CD28 transcription through the same mechanism, providing evidence that CD28 can generate a T cell receptor-independent signal with a unique biological outcome. Collectively, these data unequivocally demonstrate the critical role of the INR in the regulation of CD28 expression. T cell lines with transient expression of CD28 are invaluable in the dissection of the biochemical processes involved in the transactivation of the CD28 INR, the silencing of which is a key event in the ontogenesis of senescent T cells.
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页码:29130 / 29138
页数:9
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