NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells

Area of Science:

• Immunology
• Molecular Biology
• Cellular Signaling

Background:

• 4-1BB (CD137) is a costimulatory receptor on immune cells, crucial for T cell activation and function.
• Its expression is induced upon T cell receptor (TCR) stimulation, but the underlying transcriptional mechanisms are not fully elucidated.

Purpose of the Study:

• To investigate the transcriptional machinery controlling the T cell receptor (TCR) activation-dependent induction of 4-1BB (CD137) expression.
• To identify specific transcription factors and signaling pathways involved in regulating 4-1BB promoter activity.

Main Methods:

• Utilized 5'-deletion constructs of the 4-1BB promoter linked to a luciferase reporter gene.
• Employed luciferase reporter assays, electrophoretic mobility shift assays (EMSA), and site-directed mutagenesis.
• Assessed the role of MEK and c-Jun N-terminal kinase-1 (JNK1) signaling pathways.

Main Results:

• Transcriptional elements regulating 4-1BB upregulation are located between approximately 0.9 and 1.1 kb upstream of the translational start site.
• Electrophoretic mobility shift assays and mutagenesis confirmed the involvement of nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1) binding sites.
• MEK and JNK1 activities were essential for the activation-dependent upregulation of 4-1BB.

Conclusions:

• NF-kappaB and AP-1 are critical transcription factors mediating the TCR stimulation-dependent transcriptional regulation of the 4-1BB promoter.
• The findings provide insights into the molecular mechanisms governing 4-1BB expression, essential for adaptive immune responses.