Abstract
In addition to antigen-driven signals, T cells need co-stimulatory signals for robust activation. Several receptors, including members of the tumor necrosis factor receptor superfamily (TNFRSF), can deliver co-stimulatory signals to T cells. Thioredoxin interacting protein (TXNIP) is an important inhibitor of glucose uptake and cell proliferation, but it is unknown how TXNIP is regulated in T cells. The aim of this study was to determine expression levels and regulation of TXNIP in human T cells. We found that naïve T cells express high levels of TXNIP and that treatment of blood samples with TNF results in rapid down-regulation of TXNIP in the T cells. TNF-induced TXNIP down-regulation correlated with increased glucose uptake. Furthermore, we found that density gradient centrifugation (DGC) induced down-regulation of TXNIP. We demonstrate that DGC induced TNF production that paralleled the TXNIP down-regulation. Treatment of blood with toll-like receptor (TLR) ligands induced TNF production and TXNIP down-regulation, suggesting that damage-associated molecular patterns (DAMPs), such as endogenous TLR ligands, released during DGC play a role in DGC-induced TXNIP down-regulation. Finally, we demonstrate that TNF-induced TXNIP down-regulation is dependent on caspase activity and is caused by caspase-mediated cleavage of TXNIP.
Highlights
T cells circulate the body in a resting, naïve state until they recognize specific antigen/MHC complexes
Previous studies have found that TNF can induce Thioredoxin interacting protein (TXNIP) down-regulation in macrophages and cell lines[30,33,34], and that TXNIP acts as an inhibitor of glucose uptake, tumor cell proliferation and cell cycle progression[26,30,31,41]
Incubation of the peripheral blood mononuclear cells (PBMC) for 4 h before purification of the T cells resulted in an almost complete disappearance of TXNIP (Fig. 1D, 4 h PBMC). From these observations we concluded that purification of PBMC initiates TXNIP down-regulation in T cells and that the effect of TNF on TXNIP expression in T cells should be determined by incubating unprocessed blood samples with TNF
Summary
T cells circulate the body in a resting, naïve state until they recognize specific antigen/MHC complexes. For full activation and proliferation, naïve T cells need co-stimulatory signals in addition to antigen-driven signals. Combined with the observation that TXNIP binds and inhibits the reductase activity of thioredoxin[37], this suggested that TXNIP plays important roles in regulation of T cell responses. One study indicated that TXNIP is expressed at high levels in naïve human T cells and that it is down-regulated in T cells activated through the T cell receptor[27]. We provide first evidence that TNF induces rapid down-regulation of TXNIP and a concomitant increase in glucose uptake in naïve T cells. Our data show that TXNIP is strongly expressed in naïve T cells but rapidly down-regulated by TNF, which suggests that TNF might act as a co-stimulatory molecule for T cells by inducing down-regulating of TXNIP
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