Review
CD26, let it cut or cut it down

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Abstract

The costimulatory properties of CD26 have been studied extensively and significant progress has been made in unravelling the complex nature of this molecule. Here, we summarize recent findings on molecular and functional characteristics of CD26. We argue that a multidisciplinary approach might reveal the molecular events underlying the role of CD26 in HIV infection and immune, inflammatory and endocrine responses.

Section snippets

Structure of CD26

The complete cDNA and derived amino acid sequence for human CD26 was first published in 1992 (Ref. 4). The CD26 gene5 (Box 1) encodes a type II transmembrane protein of 766 amino acids, which is anchored to the lipid bilayer by a single hydrophobic segment located at the N-terminus (Fig. 1), and has a short cytoplasmic tail of six amino acids. A flexible stalk links the membrane anchor to a large glycosylated region, a cysteine-rich region and a C-terminal catalytic domain. Alignment of the

Multiple alliances but no known partner

In addition to its exopeptidase activity (discussed below), CD26 specifically binds several proteins outside its substrate-binding site. In contrast to other costimulatory molecules on the T cell, such as CD28, no counter-receptor has been identified for CD26.

CD26 expression

CD26 is strongly expressed on epithelial cells (kidney proximal tubulus, intestine, bile duct) and on several types of endothelial cells and fibroblasts as well as leukocyte subsets24 (see below). This rather wide expression of the gene encoding CD26/DPP IV is in contrast to the restricted expression of the related FAP-α gene. A detailed characterization of the promotor regions of both genes might help in understanding the regulation of CD26 synthesis. An interesting feature of CD26 traffic is

(Co)stimulation via CD26

In general, the activation of T cells requires at least two signals. The first is provided by stimulation of the T-cell receptor (TCR) complex by specific peptide antigen or mAb. The second signal can be delivered by triggering costimulatory surface molecules that, similar to adhesion molecules, belong to the group of ‘accessory molecules’ that are involved in a series of antigen non-specific interactions between antigen-presenting cells (APCs) and T cells during a physiological activation

Cutting down CD26 enzymatic activity

Another approach to studying the role of the enzymatic activity of CD26 in immune regulation involves the development and introduction of specific inhibitors in appropriate in vitro and in vivo settings (Ref. 46 and reviewed in Ref. 47). However, their use requires monitoring for possible toxic effects as well as inclusion of appropriate controls. As more specific inhibitors become available that significantly differ in chemical structure or mechanism of action, comparative studies are

Natural substrates of CD26: cutting makes the difference

The immunosuppressive effect of CD26 enzyme inhibitors, as well as the observation that soluble wild-type CD26 enhances impaired responses to recall antigen in vitro54, 55, indicate that a further search for its possible biological substrates would be useful. Several cytokines, hematopoietic growth factors, neuropeptides and hormones share the X-Pro or X-Ala motif at their N-terminus. As with N-terminal cyclization, the presence of a proline near the N-terminus serves as structural protection

Chemokines as targets for CD26 activity

Based on the above evidence, it seemed reasonable that chemokines, a family of relatively small cytokines that induce leukocyte migration (chemotaxis), might be substrates for this highly selective ectopeptidase. The importance of the N-terminal region of chemokines for signaling through binding to their receptors, as well as the natural occurrence of N-terminally truncated chemokines, prompted a study of chemokine processing by CD26. Along with others, we have reported that several chemokines

HIV and CD26: dual role?

Since the identification of HIV-1, the relation between CD26 expression and AIDS has been studied with varying intensity. It is now well recognized that HIV-infected individuals have significantly lower percentages of CD26bright cells than non-infected controls28, 37. Because CD26bright T cells play a crucial role in the immune response upon recall antigen challenge, the early and selective loss of CD26+ cells has been related to the progressive impairment of the immune function in these

Conclusion

CD26/DPP IV is a large, multifunctional glycoprotein, whose role in immunology has mainly been studied in T-cell biology. Recently, progress has been made in defining different epitopes, but no three-dimensional structure is yet available. CD26/DPP IV-mediated truncation of natural substrates can alter their function, stressing the necessity of measuring bioactive forms instead of immunoreactive ‘pools’ of modified peptides. The nature of its substrates, together with its regulated expression

Acknowledgements

We gratefully acknowledge our colleagues who have contributed to this field and thank E. Bosmans for continuing support and A. Muys for help with the illustrations. Discussions with J.W. Kupiec-Weglinski (The Dumont-UCLA Transplant Center), G. Vanham and L. Kestens (Institute for Tropical Medicin of Antwerp) have been invaluable for our research. Financial support for the authors' research was provided by the Fund for Scientific Research (FWO-Vlaanderen) and the Deutsche Forschungsgemeinschaft

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