Dipeptidyl peptidase IV (DP IV), an ectoenzyme in the cell membrane of T lymphocytes, is an important constituent in the process of lymphocyte activation. This conclusion is drawn from the following observations: (a) Proliferation of peripheral blood lymphocytes induced by mitogenic lectins (phytohemagglutinin, concanavalin A, pokeweed mitogen) is suppressed in the presence of DP IV inhibitors. This effect is specific and applies to an irreversible suicide inhibitor as well as to a competitive one in a dose-dependent fashion. (b) Inhibition of DNA synthesis was also induced by a polyclonal anti-DP IV immunoglobulin. (c) As a consequence of impaired T cell function the production of immunoglobulins by pokeweed mitogen-stimulated lymphocytes is also markedly reduced in the presence of DP IV inhibitors.

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Glycylproline p-nitroanilide is hydrolysed in lymphocytes from human blood exclusively by dipeptidyl peptidase IV. This was demonstrated by specific inhibition with N-alanylprolyl-O-(4-nitrobenzoyl)hydroxylamine and di-isopropyl phosphorofluoridate and by studying the membrane localization of dipeptidyl peptidase IV and determining specific dipeptidyl peptidase II activity. Additional evidence that dipeptidyl peptidase IV is a marker for T-lymphocytes, obtained from determinations of biochemical activity on intact lymphocyte preparations and correlation studies with other T-cell markers, is also presented.

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Specific inhibitors of the membrane-bound dipeptidyl peptidase IV (DP IV) and polyclonal antibodies against this enzyme were used to investigate the relationships between DP IV activity and the production and action of T cell-derived lymphokines. Production of interleukin 2 (IL-2) and gamma interferon by mitogen plus phorbol ester-stimulated mononuclear cells from human blood was found to be reduced in the presence of N-Ala-Pro-O-(nitrobenzoyl-)-hydroxylamine, epsilon-(4'-nitro) benzoxycarbonyl-Lys-Pro, and anti-(DP IV) immunoglobulin in a dose-dependent manner. Moreover, the proliferative response of mitogen-stimulated mononuclear cells to IL-2 is impaired in the presence of DP IV inhibitors. Therefore it is suggested that the membrane peptidase DP IV is involved in the induction and activation of cytokines controlling lymphocyte proliferation.