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

Abstract

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-␤1. 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.

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

“…In contrast, recent reports found elevated numbers of CD26 ϩ CD4 ϩ T cells in peripheral blood and cerebrospinal fluid from patients with multiple sclerosis (MS), and suggested that CD26/DP IV mediates T cell recruitment to airways in a rat asthma model (12)(13)(14)(15)(16)(17)(18). Moreover, in vitro and in vivo studies conducted with potent synthetic inhibitors identified CD26/DP IV as a target for immunosuppressive therapy (4,19,20). Due to their suppression of leukocyte functions, synthetic inhibitors of CD26/DP IV demonstrated profound therapeutic effects in several animal models of human diseases, including rheumatoid arthritis, transplantation, and MS (6 -8, 21), but the underlying mechanisms are still elusive.…”

“…Specifically, we tested the hypothesis that the CD26 molecule plays a critical regulatory role in autoimmune disease by serving as a target for naturally occurring inhibitory ligands that were previously identified, including ubiquitously expressed proteins such as the thromboxane A2 receptor (TXA2-R) (3,4,19,24). By demonstrating systemic deregulation of Th1 immune responses and exacerbation of EAE in mice lacking CD26/DP IV, we provide evidence for a nonredundant role of this molecule as a negative regulator of T cell functions during inflammatory immune responses in vivo.…”

“…Although T cells can directly interact with ligands through their surface-expressed CD26/DP IV molecule (19,22,23), a secreted form of the DP IV enzyme is able to selectively truncate many soluble mediators of immune functions (1)(2)(3)(4)(5)24). Two structurally and functionally distinct groups of ligands for CD26/DP IV have been identified, as follows: 1) bona fide substrates that are hydrolyzed by DP IV, including the chemokines CXCL12 (stromal cell-derived factor-1), CCL5 (RANTES), or substance P or neuropeptide Y (3,5,24), and 2) inhibitory ligands that are not cleaved by DP IV, such as the HIV Tat protein and synthetic inhibitors (4,19).…”

“…Notably, many ligands engaging membrane CD26/DP IV at the T cell surface can efficiently induce the regulatory cytokine TGF-␤1 in T cells and inhibit T cell activation and DNA synthesis (8,19,23). Thus, we and others have shown that inhibition of CD26/DP IV activity on human or mouse T cells by synthetic or naturally occurring inhibitory ligands results in TGF-␤1-mediated suppression of IL-2 and IFN-␥ production, as well as in suppression of T cell proliferation in vitro (4,8,19,23).…”

Improved stability, insulin-releasing activity and antidiabetic potential of two novel N-terminal analogues of gastric inhibitory polypeptide: N-acetyl-GIP and pGlu-GIP

“…As with GLP-1 degradation, this is due mainly to rapid cleavage by a highly specific aminopeptidase, dipeptidyl peptidase IV (DPP IV; EC.3.4.14.5) a member of the prolyl oligopeptidase family of serine proteases [17]. DPP IV is expressed ubiquitously in mammalian tissues and organs [18] with a specificity for removing dipeptides from the amino terminus of a wide range of peptides with penultimate proline, alanine and hydroxyproline residues [19,20]. DPP IV is in close contact with hormones circulating in the blood, located on endothelial cells of the blood vessels and, moreover, it is found as a soluble enzyme in blood plasma [21].…”