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 dipept idyl 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 TV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-termi nal three positions of the Tat(1-9) sequence, we found that tryptophan in p osition 2 strongly improves DP IV inhibition. NMR spectroscopy and molecula r modeling show that the effect of Trp(2)-Tat(1-9) could not be explained b y significant alterations in the backbone structure and suggest that trypto phan 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 an tigen-presenting cells, namely monocytes, The N-terminal nonapeptide of TXA 2-R, TXA2-R(1-9), inhibits DP IV and DNA synthesis and IL-2 production of t etanus toroid-stimulated peripheral blood mononuclear cells. Moreover, TXA2 -R(1-9) induces the production of the immunosuppressive cytokine transformi ng growth factor-pi. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP TV and may modulate T cell activat ion via DP IV/CD26 inhibition.