Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

Abstract

SummaryCD26/DPP4 (dipeptidyl peptidase 4/DP4/DPPIV) is a surface T cell activation antigen and has been shown to have DPP4 enzymatic activity, cleaving-off amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. It plays a major role in glucose metabolism by Nterminal truncation and inactivation of the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). In 2006, DPP4 inhibitors have been introduced to clinics and have been demonstrated to efficiently enhance the endogenous insulin secretion via prolongation of the half-life of GLP-1 and GIP in patients. However, a large number of studies demonstrate clearly that CD26/DPP4 also plays an integral role in the immune system, particularly in T cell activation. Therefore, inhibition of DPP4 might represent a double-edged sword. Apart from the metabolic benefit, the associated immunological effects of long term DPP4 inhibition on regulatory processes such as T cell homeostasis, maturation and activation are not understood fully at this stage. The current data point to an important role for CD26/DPP4 in maintaining lymphocyte composition and function, T cell activation and co-stimulation, memory T cell generation and thymic emigration patterns during immune-senescence. In rodents, critical immune changes occur at baseline levels as well as after in-vitro and in-vivo challenge. In patients receiving DPP4 inhibitors, evidence of immunological side effects also became apparent. The scope of this review is to recapitulate the role of CD26/DPP4 in the immune system regarding its pharmacological inhibition and T cell-dependent immune regulation.Keywords: autoimmunity, B cell, cell activation, chemokines, T cells Structure and characterization of CD26Originally described 50 years ago [1], the lymphocyte cell surface protein CD26 possess a dipeptidyl peptidase-4 (DPP4) activity. It cleaves dipeptides from the N-termini of oligopeptides and smaller peptides with proline or alanine at the penultimate position, as illustrated in Fig. 1b [International Union of Biochemistry and Molecular Biology (IUBMB) Enzyme Nomenclature EC 3.4.14.5].CD26/DPP4 is a homodimer and an integral type II glycoprotein anchored to the membrane by its signal peptide. The primary structure consists of a short six amino acid cytoplasmic tail, a 22 amino acid transmembrane, a 738 amino acid extracellular portion comprised of a flexible stalk, glycosylation-rich region, cysteine-rich region and catalytic region with the catalytic triad Ser 630 , Asp 708 and His 740 (Fig. 1e). Recent studies have revealed that the transmembrane region contributes to enzyme activity and quaternary structure by dimerization [2]. The crystal structure of human CD26/DPP4 has been elucidated to reveal two domains: an eight-bladed propeller and an a/b-hydrolase domain. The propeller is open and consists of two subdomains made up of blades II-V and VI-VIII for the glycosylation-rich and cysteine-rich regions, respectively (Fig. 1d). Most monoclonal anti-CD26/DPP4 antibodies,...

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…The proline-specific DPP4 also modulates the bioactivity of several chemokines, as well as neuropeptides and peptide hormones such as neuropeptide Y (NPY), substance P (SP), glucagon-like peptide (GLP)21, GIP and glucagon. Indeed, several DPP4 inhibitors (gliptins) are currently on the market as anti-diabetic drugs [8][9][10]. Thus it is involved in glucose homeostasis, food uptake, anxiety, stress, cardiovascular, nociception and chemotaxis.…”

“…1. Furthermore, DPP4 also internalizes upon association with binding partners such as CXCR 4 and M6P/IGFII, recycling of terminal carbohydrates and assembled to lipid rafts [8,9] …”

“…DPP8 is up-regulated upon T cell activation, whereas DPP9 plays a role in antigen trimming for antigen presentation [2,39,40]. DPP4/ CD26 is involved in T cell activation, T cell signalling and T cell differentiation due to its interactions with ADA, CD45, caveolin-1, CARMA-1 and M6P/IGFII-R [9]. These processes are regulated by the cytokines IL-2, IL-6, IL-10, IL-12, IL-17, IL-29, IFN-g and TGF-b, as well as compartmentation of DPP4/CD26 to either lipid rafts or internalization [8,9,48,88,89,[91][92][93].…”

“…DPP4 (CD26). DPP4 (CD26) is the best-known DASH protein and has been described in detail elsewhere [7][8][9]. …”

Dipeptidyl Peptidase-IV Inhibition for the Treatment of Cardiovascular Disease ― Recent Insights Focusing on Angiogenesis and Neovascularization ―

“…18 It is established that inhibition of DPP-IV can promote insulin secretion and improve glucose tolerance in humans via the GLP-1-dependent pathway. It was also shown that DPP-IV inhibitors can improve glucose tolerance in Glp1r −/− mice, 19 suggesting that DPP-IV has its own biological roles independent of GLP-1.…”