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

Abstract

Dipeptidyl peptidase (DPP) 4 (CD26, DPP4) is a multi-functional protein involved in T cell activation by co-stimulation via its association with adenosine deaminase (ADA), caveolin-1, CARMA-1, CD45, mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) and C-X-C motif receptor 4 (CXC-R4). The proline-specific dipeptidyl peptidase also modulates the bioactivity of several chemokines. However, a number of enzymes displaying either DPP4-like activities or representing structural homologues have been discovered in the past two decades and are referred to as DPP4 activity and/or structure homologue (DASH) proteins. Apart from DPP4, DASH proteins include fibroblast activation protein alpha (FAP), DPP8, DPP9, DPP4-like protein 1 (DPL1, DPP6, DPPX L, DPPX S), DPP4-like protein 2 (DPL2, DPP10) from the DPP4-gene family S9b and structurally unrelated enzyme DPP2, displaying DPP4-like activity. In contrast, DPP6 and DPP10 lack enzymatic DPP4-like activity. These DASH proteins play important roles in the immune system involving quiescence (DPP2), proliferation (DPP8/DPP9), antigen-presenting (DPP9), co-stimulation (DPP4), T cell activation (DPP4), signal transduction (DPP4, DPP8 and DPP9), differentiation (DPP4, DPP8) and tissue remodelling (DPP4, FAP). Thus, they are involved in many pathophysiological processes and have therefore been proposed for potential biomarkers or even drug targets in various cancers (DPP4 and FAP) and inflammatory diseases (DPP4, DPP8/DPP9). However, they also pose the challenge of drug selectivity concerning other DASH members for better efficacy and/or avoidance of unwanted side effects. Therefore, this review unravels the complex roles of DASH proteins in immunology.

Keywords: CD26; DPP4 activity and/or structure homologue proteins (DASH); antigen presentation/processing; co-stimulation; signal transduction.

Figure 1

Cellular compartmentation of dipeptidyl peptidase (DPP)4‐like enzymes. DPP4 and fibroblast activation protein alpha (FAP) are located either as homodimers or heteromeric complex on the plasma membrane or shedded into the serum. DPP2, a homodimer, is distributed as a zymogen in secretory vesicles or lysosome. DPP8 and DPP9 are also homodimers and located cytosolically. , glycosylation.

Figure 2

Involvement of dipeptidyl peptidase (DP)4‐like enzymes in T cell effector response. (a) Naive CD4 T cells are protected by DP2. Antigen‐presenting cells (APC) stimulate and activate naive CD4 T cells. (b) Secretion of interleukin (IL)‐2 results in clonal expansion, yielding T helper type 0 (Th0) cells. Enzymatic activities of DP8 and DP9 are required for this process. (c) Secretion of IL‐12 and IL‐4 results in the differentiation of Th1 and Th2 effector cells, respectively. Differentiation into Th1 cells initiates the up‐regulation of DP4 expression. A small subset of CD26^bright memory T cells already expresses high amounts of CD26. Upon antigen stimulation, CD26^bright memory T cells augment the Th1 and Th2 response by secreting interferon (IFN)‐γ, IL‐12, IL‐4, IL‐5 and IL‐10, respectively. Differentiation into Th2 cells results in only a slight up‐regulation of CD26. The DP4 activity is equal in both T effector cells, due probably to specific DP4 isoforms or DP8 and/or DP9. (d) Differentiated T effector cells secrete specific cytokines that induce differentiation of leucocytes, resulting in cellular response by Th1 and humoral by Th2 effector cells. Leucocytes expressing DP4, DP2 or DP8/9 are indicated. Green arrow = stimulation; red arrow = suppression. 16, 17, 28, 31, 39, 40, 41, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 102, 104.