The role of dipeptidyl peptidase IV (DP IV, CD26) in T cell activation and multiple sclerosis

Abstract

The ectoenzyme dipeptidyl peptidase IV (DP IV; E.C. 3.4.14.5; CD26) plays a crucial role in T cell activation, representing a new type of costimulatory T cell structure. Effectors of DP IV-like activity, including naturally occurring and specific synthetic inhibitors, suppress DNA synthesis as well as cytokine production (IL-2, IL-10, IL-12, IFN-γ) of stimulated T cells. These effects are in part caused by the immunosuppressive cytokine TGF-β1, leading to blockade of the cell cycle at the restriction point G1/S via p27kip. At the same time, DP IV inhibitors provoke tyrosine phosphorylation and p38 MAP kinase activation. Elevated numbers of CD26+ T cells were observed in patients with autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (MS). The expression of DP IV/CD26 in resting T cell clones derived from patients with MS was found to be 3- to 4-fold higher than on resting peripheral blood T cells from healthy persons. In myelin-specific T cells from MS patients, DP IV inhibitors suppress DNA synthesis, as well as IFN-γ, IL-4 and TNF-α production. Moreover, in experimental autoimmune encephalomyelitis (EAE), a well characterized CD4+ T cell-mediated autoimmune disease leading to CNS inflammation and demyelinization, administration of a DP IV/CD26 inhibitor prevents clinical and neuropathological signs of EAE and suppresses ongoing disease. This review summarizes evidence for the role of DP IV enzyme activity in regulation of T cell activation, outlines signal transduction mechanisms used or affected by this enzyme and provides support for the concept of a novel peptidase-based immunosuppressive approach to treat autoimmune diseases like MS.