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J. Biol. Chem., Vol. 279, Issue 28, 29130-29138, July 9, 2004

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Tumor Necrosis Factor- and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription^*

Dorothy E. Lewis, Maria Merched-Sauvage, Jörg J. Goronzy, Cornelia M. Weyand, and Abbe N. Vallejo¶||

From the Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, and ^¶Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905

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- 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.

Received for publication, February 27, 2004 , and in revised form, April 27, 2004.

^* This work was supported by the Mayo Foundation and by National Institutes of Health research Grants R01-AG22379 (to A. N. V.), R01-AG15043 (to J. J. G.), and R37-AI36682 (to D. E. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Children's Hospital of Pittsburgh, 2122 Rangos Research Center, University of Pittsburgh School of Medicine, 3705 Fifth Ave., Pittsburgh, PA 15213. E-mail: abbe.vallejo{at}chp.edu.

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