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

Abstract

CD26/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 N-terminal 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: B cell; T cells; autoimmunity; cell activation; chemokines.

Figure 1

Primary and quaternary structure of human dipeptidyl peptidase 4 (DPP4), based on Protein Data Bank: 1W1I. (a) Primary structure of DPP4 subunit, consisting of an intracellular tail (aa 1–6), transmembrane region (aa 7–28), flexible stalk (aa 29–39), glycosylated region (aa 101–350), cysteine‐rich region (aa 55–100, 351–497), and catalytic region (aa 506–766). , N‐glycosylation; , potential unoccupied N‐glycosylation; , cysteine residues involved in S‐bridges; red numbers and letters indicate the catalytic triad. (b) Substrate specificity of DPP4. X_aa and Y_aa indicate any amino acid. Decreasing font of amino acid at P₁ position represents declining rate of hydrolysis. Amino acids crossed out must not occupy P₁′. Arrow indicates site of cleavage. (c) quaternary structure of homodimeric human recombinant DPP4 as determined by Weihofen et al., 2004, showing the α/β‐hydrolase domain (aa 39–51 and 506–766) in green and propeller domain (aa 55–497) with the glycosylation‐rich subdomain (red) and the cystein‐rich subdomain (blue). (d) Propeller domain viewed from the top, illustrating the eight propeller blades designated with roman numbers and two subdomains. (e) Active site zoomed in, depicting the residues involved in catalysis, catalytic triad Ser₆₃₀, Asp₇₀₈, His₇₄₀ are shown in red, Tyr₅₄₇ responsible for oxyanion hole in brown, Tyr₆₆₂ and Tyr₆₆₆ forming the hydrophobic pocket in grey, Arg₁₂₅ and Asn₇₁₀, contributing to an electrostatic sink in orange and blue, respectively, and Glu₂₀₅ and Glu₂₀₆ ensuring N‐terminal anchoring in pale green. S–S bridges are illustrated in yellow and carbohydrates in orange. Structures were drawn with PyMOL^TM 2008 DeLano Scientific LLC, using Protein Data Base: 1W1I 7.

Figure 2

Structure, properties and functions of dipeptidyl peptidase 4 (DPP4) sialylation 10, 11, 12, 16, 17, 18, 20.

Figure 3

Physiological and pathological processes influenced by dipeptidyl peptidase 4 (DPP4) 4, 92, 93. (a) Summary of physiological roles of DPP4; (b) pathophysiological role of DPP4 with either altered expression and/or activity.

Figure 4

A model of CD26 interacting with caveolin‐1 resulting in T cell co‐stimulation and activation as proposed by Ohnuma et al. 188: after antigen uptake via caveolae by antigen‐presenting cells (APCs), caveolin‐1 is exposed on the cell surface and aggregates in the immunological synaps in lipid rafts. Consequently, caveolin‐1 binds to CD26 and is phosphorylated, leading dissociation of interleukin (IL)−1 receptor‐associated kinase 1 (IRAK‐1) and Tollip. This lead to activation of nuclear factor (NF)‐κB and results in CD86 up‐regulation, supporting the immunological synapse and thus T cell co‐stimulation. In T cells, after caveolin‐1 to CD26 binding, (CARD11) CARMA1 is recruited to the cytosolic portion of CD26. Activation of NF‐κB lead to T cell proliferation and IL‐2 production.

Figure 5

Crystal structure of human dipeptidyl peptidase 4 (DPP4) and bovine adenosine deaminase (ADA) obtained from Protein Data Bank: 1W1I. (a) DPP4 crystal structure associated with bovine ADA at its glycosylation‐rich region of the propeller domain. (b) Top view of propeller domain, showing ADA binding site at bladea 4 and 5 as well as ADA interactions with carbohydrates of N229. (c) Caveolin‐1 binding site at aa 201–210 and Ser₆₃₀ 7.