CD26 has proved interesting in the fields of immunology, endocrinology, cancer biology and nutrition owing to its ubiquitous and unusual enzyme activity. This dipeptidyl aminopeptidase (DPP IV) activity generally inactivates but sometimes alters or enhances the biological activities of its peptide substrates, which include several chemokines. CD26 costimulates both the CD3 and the CD2 dependent T-cell activation and tyrosine phosphorylation of TCR/CD3 signal transduction pathway proteins. CD26 in vivo has integral membrane protein and soluble forms. Soluble CD26 is at significant levels in serum, these levels alter in many diseases and soluble CD26 can modulate in vitro T-cell proliferation. CD26, being an adenosine deaminase binding protein (ADAbp), functions as a receptor for ADA on lymphocytes. The focus of this review is the structure and function of CD26 and the influence of its ligand binding activity on T-cell proliferation and the T cell costimulatory activity of CD26.

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Fibroblast activation protein (FAP) is best known for its heightened expression in tumour stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. FAP expression is difficult to detect in non-diseased adult organs, but is greatly upregulated in sites of tissue remodelling, which include liver fibrosis, lung fibrosis, atherosclerosis, arthritis, tumours and embryonic tissues. Due to its restricted expression pattern and dual enzymatic activities, FAP is emerging as a unique therapeutic target. However, methods to exploit and target this protease are advancing more rapidly than knowledge of the fundamental biology of FAP. This review highlights this imbalance, emphasising the need to better define the substrate repertoire and expression patterns of FAP to elucidate its role in biological and pathological processes.

CD26 is a leukocyte activation marker that possesses dipeptidyl peptidase IV activity but whose natural substrates and immunological functions have not been clearly defined. Several chemo-kines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. The truncated RANTES(3–68) lacked the ability of native RANTES(1–68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor. Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity. RANTES(3–68) showed a reduced activity, relative to that of RANTES(1–68), with cells expressing the recombinant CCR1 chemokine receptor, but retained the ability to stimulate CCR5 receptors and to inhibit the cytopathic effects of HIV-1. Our results indicate that CD26-mediated processing together with cell activation–induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.

DP (dipeptidyl peptidase) IV is the archetypal member of its six-member gene family. Four members of this family, DPIV, FAP (fibroblast activation protein), DP8 and DP9, have a rare substrate specificity, hydrolysis of a prolyl bond two residues from the N-terminus. The ubiquitous DPIV glycoprotein has proved interesting in the fields of immunology, endocrinology, haematology and endothelial cell and cancer biology and DPIV has become a novel target for Type II diabetes therapy. The crystal structure shows that the soluble form of DPIV comprises two domains, an alpha/beta-hydrolase domain and an eight-blade beta-propeller domain. The propeller domain contains the ADA (adenosine deaminase) binding site, a dimerization site, antibody epitopes and two openings for substrate access to the internal active site. FAP is structurally very similar to DPIV, but FAP protein expression is largely confined to diseased and damaged tissue, notably the tissue remodelling interface in chronically injured liver. DPIV has a variety of peptide substrates, the best studied being GLP-1 (glucagon-like peptide-1), NPY (neuropeptide Y) and CXCL12. The DPIV family has roles in bone marrow mobilization. The functional interactions of DPIV and FAP with extracellular matrix confer roles for these proteins in cancer biology. DP8 and DP9 are widely distributed and indirectly implicated in immune function. The DPL (DP-like) glycoproteins that lack peptidase activity, DPL1 and DPL2, are brain-expressed potassium channel modulators. Thus the six members of the DPIV gene family exhibit diverse biological roles.

Fibroblast activation protein (FAP) is a plasma membranebound atypical serine protease of the prolyl oligopeptidase gene family and is expressed at sites of tissue remodelling. 1,2 FAP was initially described as the cell surface antigen recognized by monoclonal antibody (mAb) F19 on subsets of human astrocytoma and sarcoma cell lines in vitro. 3,4 Subsequent immunohistochemical studies demonstrated that FAP, while not expressed in most normal adult human tissues, is strongly expressed by the reactive tumor stromal fibroblasts surrounding the newly formed blood vessels of epithelial cancers. 5 In addition, FAP-expressing reactive fibroblasts are found in the granulation tissue of healing wounds and in certain fetal mesenchymal tissues. 2,5 Based on the highly selective expression of FAP, in vivo targeting of the tumor stromal compartment has been achieved with radiolabeled anti-FAP mAb F19 in patients with colorectal cancer. 6 Molecular cloning and sequence analysis of a human FAP cDNA and biochemical studies with FAP-specific mAbs have identified the gene product as an N-glycosylated, type II integral membrane protein with a molecular weight of about 95,000, comprising a large carboxy-terminal extracellular domain, a hydrophobic transmembrane segment, and a short cytoplasmic tail. 2 Dimeric and higher-molecular-weight complexes of FAP have been described.

Dipeptidyl peptidase (DPP) IV has roles in T‐cell costimulation, chemokine biology, type‐II diabetes and tumor biology. Fibroblast activation protein (FAP) has been implicated in tumor growth and cirrhosis. Here we describe DPP8, a novel human postproline dipeptidyl aminopeptidase that is homologous to DPPIV and FAP. Northern‐blot hybridization showed that the tissue expression of DPP8 mRNA is ubiquitous, similar to that of DPPIV. The DPP8 gene was localized to chromosome 15q22, distinct from a closely related gene at 19p13.3 which we named DPP9. The full‐length DPP8 cDNA codes for an 882‐amino‐acid protein that has about 27% identity and 51% similarity to DPPIV and FAP, but no transmembrane domain and no N‐linked or O‐linked glycosylation. Western blots and confocal microscopy of transfected COS‐7 cells showed DPP8 to be a 100‐kDa monomeric protein expressed in the cytoplasm. Purified recombinant DPP8 hydrolyzed the DPPIV substrates Ala‐Pro, Arg‐Pro and Gly‐Pro. Thus recombinant DPP8 shares a postproline dipeptidyl aminopeptidase activity with DPPIV and FAP. DPP8 enzyme activity had a neutral pH optimum consistent with it being nonlysosomal. The similarities between DPP8 and DPPIV in tissue expression pattern and substrates suggests a potential role for DPP8 in T‐cell activation and immune function.

Recent data increasingly support a complex interplay between the metabolic condition diabetes mellitus and the pathologically defined nonalcoholic fatty liver disease (NAFLD). NAFLD predicts the development of type 2 diabetes and vice versa, and each condition may serve as a progression factor for the other. Although the association of diabetes and NAFLD is likely to be partly the result of a "common soil," it is also probable that diabetes interacts with NAFLD through specific pathogenic mechanisms. In particular, through interrelated metabolic pathways currently only partly understood, diabetes appears to accelerate the progression of NAFLD to nonalcoholic steatohepatitis, defined by the presence of necroinflammation, with varying degrees of liver fibrosis. In the research setting, obstacles that have made the identification of clinically significant NAFLD, and particularly nonalcoholic steatohepatitis, difficult are being addressed with the use of new imaging techniques combined with risk algorithms derived from peripheral blood profiling. These techniques are likely to be used in the diabetes population in the near future. This review examines the pathogenic links between NAFLD and diabetes by exploring the epidemiological evidence in humans and also through newer animal models. Emerging technology to help screen noninvasively for differing pathological forms of NAFLD and the potential role of preventive and therapeutic approaches for NAFLD in the setting of diabetes are also examined.