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Abstract

T cell receptor (TCR) engagement and subsequent signalling are a prerequisite to initiate a T cell immune response. In recent years, our group investigated the underlying mechanisms of TCR signalling and identified Thioredoxin-interacting protein (TXNIP) as a possible regulator of a T cell immune response. This study examined the role of TXNIP in TCR signalling. Following TCR stimulation, TXNIP expression was reduced due to accelerated proteasomal degradation as well as decreased protein synthesis. Since TXNIP is a negative regulator of Trx, activation-induced downregulation of TXNIP expression resulted in increased Trx activity. Using TXNIP knockout (KO) T cells as a model system, this study revealed that TXNIP has an impact on gene expression upon TCR engagement. By analysing stimulation-induced whole genome expression of TXNIP KO cells in comparison to control cells, this study demonstrated that TXNIP acts as a transcriptional inhibitor. TXNIP affects transcription of CD95L, GMCSF, GZMB, IFNG, IL2, TNFA and EGR2. These genes are involved in T cell activation, differentiation, cytokine signalling as well as cell death and designated as NFκB, AP1 as well as NFAT targets. Thus, TXNIP might control gene expression by regulating the activity of one or various transcription factors. Expression of CD95L upon TCR stimulation mediates activation-induced cell death (AICD) in apoptosis-sensitive T cells. In accordance with increased stimulation-induced CD95L expression, AICD was enhanced in TXNIP KO cells compared to control cells. This result underlines the important role of TXNIP in TCR signalling. Taken together, this study demonstrates that TXNIP is involved in TCR signalling by acting as transcriptional inhibitor. Hence, TXNIP might be considered as a potential therapeutic target to shape T cell responses e.g. in autoimmune or tumour diseases.