CD28 engagement by B7/BB-1 induces transient down-regulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling.

Abstract

Costimulatory molecules on the APC regulate T cell growth by providing signals that regulate responses to TCR occupancy. One such molecule is B7/BB-1, which triggers a T cell activation pathway by binding the CD28 and/or CTLA-4 cell-surface molecules. Expression and signaling activity of CD28 have been shown to increase after T cell activation by various polyclonal activators. Here we show that CD28 expression and signaling activity in activated T cells decrease after ligand binding to CD28. Stimulation of CD28 on PHA- or PMA-activated T cells by cross-linked mAb 9.3 or by co-culture with B7+ Chinese hamster ovary (CHO) cells caused a marked reduction of CD28 mRNA levels within 4 h. The decrease in CD28 mRNA was transient, and by 24 h of CD28 stimulation, CD28 mRNA was found at approximately initial levels. In contrast, CTLA-4 mRNA levels were usually up-regulated by CD28 triggering. Cell-surface expression of CD28, but not CD2 or CD3, decreased by 12 to 24 h after addition of B7+ CHO cells, but returned to initial levels or higher by 48 h. The ability of CD28 cross-linking on PMA-activated CD4+ cells to trigger calcium mobilization was also reduced by treatment with B7+ CHO cells, and remained reduced even after cell-surface expression of CD28 returned to normal levels. Thus, engagement of the CD28 receptor by its natural ligand B7/BB-1 leads to a transient down-regulation of CD28 synthesis and a prolonged unresponsiveness to CD28 signaling. This represents a novel mechanism for regulation of costimulatory signals delivered by interactions of CD28 with the B7/BB-1 counter receptor.

Baseline Numbers of Circulating CD28-negative T Cells May Predict Clinical Response to Abatacept in Patients with Rheumatoid Arthritis

“…Since downmodulation of CD28 expression can be achieved in vitro through prolonged stimulation with specific peptide antigens 7 , or with cytokines like tumor necrosis factor-α (TNF-α) 8 , it can be hypothesized that the number of circulating CD28-T cells might represent a measure of the burden of prolonged previous immune stimulation. Moreover, downmodulation of CD28 expression can also be achieved in vitro through engagement with its ligands (CD80/CD86) 9 , and since this engagement is blocked by abatacept, we hypothesized that abatacept also prevents generation of the CD28-population. Indeed, we have shown that the number of CD28-T cells is reduced after therapy with abatacept 4 , and that such a decrease is correlated with clinical response.…”