Dipeptidyl Peptidase IV in Human T Lymphocytes

Schön, E; Demuth, Hans‐Ulrich; Eichmann, E.; Horst, H.-J.; Körner, Heinz; Kopp, Jeffrey B.; Mattern, Taila; Neubert, Klaus; F, Noll; Ulmer, Artur J.; Barth, A.; Ansorge, Siegfried

doi:10.1111/j.1365-3083.1989.tb01108.x

Cited by 93 publications

(13 citation statements)

References 19 publications

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“…A similar specific inhibition of antigen-induced IL-2 production was also observed in D1.1 cell cultures (data not shown). These results were somewhat unexpected in light of the previous reports by Schon and coworkers (21)(22)(23)) that DP-IV inhibitors suppress both antigen-and mitogen-induced T-cell proliferation and IL-2 production. The reasons for this discrepancy are not clear at present.…”

Section: Methodscontrasting

confidence: 51%

“…This proposal is based on experiments in which the addition of DP-IV inhibitors and DP-IV antibodies to cell culture systems suppressed mitogenand alloantigen-induced T-cell proliferation, IL-2 production (22), and impaired T-cell-directed B-cell differentiation and immunoglobulin production (23,24). Circumstantial support for this proposal comes from the observation that a number of cytokines have DP-IV susceptible Ala-Pro N-terminal sequences, as this suggests a plausible mechanism for the proposed involvement of DP-IV in T-cell activation events.…”

mentioning

confidence: 99%

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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.

Flentke

Muñóz

Huber

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

163

108

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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.

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Section: Methodscontrasting

confidence: 51%

mentioning

confidence: 99%

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.

Flentke

Muñóz

Huber

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

163

108

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“…DPPIV enzyme activity has been implicated in antigeninduced and/or mitogen-induced T-cell proliferation and lymphokine production, by studies done with enzyme inhibitors (25)(26)(27). These studies principally suggested that DPPIV activity is necessary for certain T-cell activation pathways.…”

Section: Discussionmentioning

confidence: 99%

The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity.

Tanaka

Kameoka

Yaron

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

165

126

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T cells have been shown to express CD26, a known ectoenzyme with dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) activity in its extracellular domain. CD26 can also deliver a second costimulatory signal and contribute to T-cell activation. In an earlier study, we established CD26-transfected Jurkat T-cell lines and demonstrated that monoclonal antibody-mediated crosslinking of CD26 and CD3 induced interleukin 2 (IL-2) production. To determine the contribution of DPPIV enzymatic activity to the costimulatory activity of CD26, human CD26 cDNA was mutated so that active-site serine was replaced by alanine. The mutant CD26 antigen lacked DPPIV enzyme activity but still retained reactivity with three anti-CD26 monoclonal antibodies directed against distinct epitopes of CD26. After stimulation with a combination of anti-CD26 and anti-CD3 antibodies, wild-type CD26 (DPPIV+)-transfected Jurkat cells produced substantially more IL-2 than did mutant CD26 (DPPIV-) or CD26-control transfectants. Nevertheless, the mutant CD26-transfected cells still produced significantly more IL-2 than did CD26-control transfectants. These results suggest that DPPIV activity plays an important but not absolute role in the costimulatory activity of CD26 in this system. We also found that wild-type CD26 (DPPIV+) transfectants produced more IL-2 than mutant CD26 (DPPIVj)-transfected cells or CD26-control transfectants when triggered by stimuli not involving CD26, such as anti-CD3 and phorbol ester. These results suggest that the DPPIV activity of CD26 functions to augment the cellular responses of CD26-transfected Jurkat cells to external stimuli mediated by CD26 and/or the CD3/T-cell receptor complex, thus enhancing IL-2 production.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1996

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Recent data in the literature suggest that the HIV-1 Tat(I-86) protein exhibits immunosuppressive effects. Moreover, Tat was found to interact with dipeptidyl peptidase IV (DP IV), which is identical to the T cell activation marker CD26. Here we show that the N-terminal amino acid sequence of Tat is essential for the inhibition of DP IV-catalyzed IL-2(1-12) degradation. Nterminal modification of Tat with rhodamine prevented inhibition of enzymatic activity of DP IV as well as suppression of DNA synthesis of mitogen-stimulated human T cells. Moreover, natural peptides containing the X-X-Pro N-terminal motif of Tat also inhibited DP IV activity. These data suggest the existence of endogenous immunomodulatory oligopeptides which influence immune cell proliferation and differentiation via DP IV a~ does HIV-1 Tat.

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Dipeptidyl Peptidase IV in Human T Lymphocytes

Cited by 93 publications

References 19 publications

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.

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.

The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity.

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

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