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

Abstract

Replicative senescence of human T cells is characterized by the loss of CD28 expression, exemplified by the clonal expansion of CD28null 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 7 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.

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

“…Consistent with previous findings showing a direct repressive effect of TNF␣ on CD28 gene transcription (26,27), we found that exposure of patient-derived T cells to TNF␣ in vitro consistently resulted in the further down-regulation of CD28 (Figure 3B), showing that T cells in RA patients are responsive to TNF␣. Consistent with previous reports that TNF␣ down-regulates expression of its own receptors (33,39), our data show that T cells have decreased numbers of TNFRI and TNFRII molecules that correspond with a quantitative decrease of CD28 molecules in response to TNF␣ in vitro ( Figure 3B).…”

“…The dynamic changes in CD28 expression on CD4ϩ T cells have also been shown by other investigators to correlate with the clinical course of disease activity (44). Therefore, if such changes in the in vivo expression levels of CD28 are indeed coupled with the dysregulation of TNF␣ in RA (26)(27)(28), then anti-TNF␣ therapy (45)(46)(47) could also have an impact on CD28 expression. Our data show a significant trend toward an increase in the number of CD28 molecules in patients posttreatment (Figure 4).…”

“…T cell activation has been shown to invariably result in the down-regulation of CD28 (24,25). In addition, exposure of CD28ϩ T cells to tumor necrosis factor ␣ (TNF␣) results in the emergence of CD28 null progeny (26) due to TNF␣-induced inhibition of CD28 gene transcription (27). Long-term exposure of T cells to TNF␣ could therefore accelerate the development and accumulation of CD28 null T cells in vivo.…”

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

“…These results are predictable, since CD28 is highly sensitive to down-modulation following cellular activation (19,20). Extraarticular RA confers an increased burden of inflammation, with overexpression of endothelial HLA-DQ and IL-1, and with high serum levels of TNF␣ (34,35) known to directly inhibit CD28 gene transcription (13,25). Systemic inflammation and endothelial activation suggest an environment permissive of chronic T cell activation.…”

“…The T cell line JT is a Jurkat derivative that has low-to-nil expression of CD28 (25). In empirical studies, JT was found to express CD56 when incubated overnight with 50 ng/ml phorbol myristyl acetate (Sigma-Aldrich, St. Louis, MO), and it maintained a high expression level of CD56 for at least 2 days in the absence of phorbol myristyl acetate.…”