Down-regulation of T Cell Activation following Inhibition of Dipeptidyl Peptidase IV/CD26 by the N-terminal Part of the Thromboxane A2 Receptor

• Published in: The Journal of biological chemistry 2000-07, Vol.275 (29), p.22180-22186
• Main Authors: Wrenger, Sabine, Faust, Jürgen, Mrestani-Klaus, Carmen, Fengler, Annett, Stöckel-Maschek, Angela, Lorey, Susan, Kähne, Thilo, Brandt, Wolfgang, Neubert, Klaus, Ansorge, Siegfried, Reinhold, Dirk
• Format: Article
• Language: English
• Subjects: AIDS/HIV; CD26 antigen; human immunodeficiency virus 1; Tat protein; thromboxane A2 receptors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M002338200

Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1–9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1–9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp2-Tat(1–9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1–9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1–9) induces the production of the immunosuppressive cytokine transforming growth factor-β1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.