Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function.

Abstract

Dipeptidyl peptidase IV (DP-IV; dipeptidyl-peptide hydrolase, EC 3.4.14.5) is a serine protease with a specificity for cleaving Xaa-Pro dipeptides from polypeptides and proteins. It is found in a variety of mammalian cells and tissues, including those of lymphoid origin where it is found specifically on the surface of CD4+ T cells. Although the functional significance of this enzyme has not been established, a role in T-cell activation and immune regulation has been proposed. Here we report that Ala-boroPro and Pro-boroPro, where boroPro is the alpha-amino boronic acid analog of proline, are potent and specific inhibitors of DP-IV, having Ki values in the nanomolar range. Blocking the N terminus of Ala-boroPro abolishes the affinity of this inhibitor for DP-IV, while removal of the N-terminal residue, to give boroPro, reduces the affinity for DP-IV by 5 orders of magnitude. The dipeptide boronic acids exhibit slow-binding kinetics, while boroPro does not. We also report here that low concentrations of Pro-boroPro inhibit antigen-induced proliferation and interleukin 2 production in murine T-cell lines but do not inhibit the response of these T cells to the mitogen concanavalin A. These results indicate that DP-IV plays a role in antigen-induced, but not mitogen-induced, activation of T lymphocytes.

The N‐terminal X‐X‐Pro sequence of the HIV‐1 Tat protein is important for the inhibition of dipeptidyl peptidase IV (DP IV/CD26) and the suppression of mitogen‐induced proliferation of human T cells

“…cytokine production, B cell differentiation, and immunoglobulin secretion [12][13][14][15][16][17]. However, the function of DP IV in the proliferation and differentiation processes has not been resolved yet.…”

Effect of CD26/dipeptidyl peptidase IV on Jurkat sensitivity to G2/M arrest induced by topoisomerase II inhibitors

“…CD26 is also involved in T-cell activation, owing to its association with CD45, mannose 6-phosphate/insulin-like growth factor II receptor and adenosine deaminase (ADA) (Morimoto et al, 1989;Dang et al, 1990aDang et al, -d, 1991Torimoto et al, 1991;Kameoka et al, 1993;Morrison et al, 1993;Ikushima et al, 2000). Additionally, its DPPIV enzyme activity has a key role in various aspects of T-cell activation, as demonstrated by studies using DPPIV inhibitors, soluble CD26/DPPIV molecules or CD26 genetic mutants (Flentke et al, 1991;Tanaka et al, 1993Tanaka et al, , 1994Steinbrecher et al, 2001). Besides its involvement in normal T-cell function, CD26 may also have a role in the development of certain tumors (Tanaka et al, 1995;Stecca et al, 1997;Bauvois et al, 1999;Dang and Morimoto, 2002).…”

Enhancement of antigen-induced T-cell proliferation by soluble CD26/dipeptidyl peptidase IV.

“…Considerable evidence suggests the involvement of CD26 in T-cell activation and function (6)(7)(8)(9). Crosslinking of CD26 and CD3 with solid-phase immobilized mAbs can induce T-cell costimulation and interleukin 2 (IL-2) production by human CD4+ T cells in the absence of antigen-presenting cells (6).…”