Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.
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 Trp(2)-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-beta1. 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.
Wrenger
S
S
Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany. sabine.wrenger@medizin.uni-magdeburg.de
Faust
J
J
Mrestani-Klaus
C
C
Fengler
A
A
Stockel-Maschek
A
A
Lorey
S
S
Kahne
T
T
Brandt
W
W
Neubert
K
K
Ansorge
S
S
Reinhold
D
D
D018819:Dipeptidyl Peptidase 4 / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D015696:Gene Products, tat / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D017482:Receptors, Thromboxane / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D015696:Gene Products, tat; D008024:Ligands; D017482:Receptors, Thromboxane; D018819:Dipeptidyl Peptidase 4