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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

CD26 (dipeptidyl peptidase IV/DPP IV/adenosine deaminase binding protein/ADAbp) is a multifunctional type II cell surface glycoprotein widely expressed on T cells, B cells and natural killer (NK) cells [1–5] as well as on epithelial, endothelial and acinar cells of a variety of tissues [6–10]. Only low levels of CD26 are found on resting lymphocytes, its expression being strongly upregulated following activation [1, 3, 11]. In addition to the integral membrane form, a soluble form of CD26 occurs in serum [12–15].

The significance of CD26 in T-cell function is best indicated by the enhancement of CD3 and CD2 dependent activation and proliferation by anti-CD26 antibodies [1, 2, 11, 16–25]. Only CD4+ cells that coexpress CD26 can provide helper functions to activate cytotoxic T cells [1, 2, 19] and induce immunoglobulin (Ig) synthesis by B cells [26, 27]. CD26 modulates T-cell proliferation by interacting with the CD3 signalling pathway [28]. Soluble recombinant human CD26 (srhCD26) has been found to influence proliferation in stimulated human T cells [29].

CD26 has three functions: (1) ADA binding; (2) peptidase activity; and (3) extracellular matrix binding, all of which can influence T-cell proliferation and chemotaxis. CD26 has a postproline dipeptidyl aminopeptidase activity (DPP IV, EC 3.4.14.5) preferentially cleaving X-proline or X-alanine dipeptides from the N-terminal of polypeptides [30, 31]. DPP IV is a member of the prolyl oligopeptidase (POP; EC 3.4.21.26) family, a group of atypical serine proteinases able to hydrolyse the prolyl bond [32–34]. The natural substrates of DPP IV include several chemokines, thus contributing to the regulation of leucocyte migration [31, 35–38].

The potential roles of CD26 in human immunodeficiency virus (HIV) infection relate to altering the HIV-inhibiting capacities of the chemokines CCL5 (regulated on activation normal T cell expressed and secreted (RANTES)) and CXCL12 (stromal derived factor-1α and -1β) [39], binding gp120 of HIV [40] and binding the HIV tat protein [41, 42]. These phenomena may contribute to the selective reduction in the numbers of CD4+CD26+ cells in HIV infection [43–47]. Conflicting reports on whether intact versus DPP IV-truncated CCL5 and CXCL12 differ in their abilities to inhibit HIV infection [35, 48–50] do not explain the loss of CD4+CD26+ cells. Perhaps an undiscovered chemokine will prove to be the most important contributor to this phenomenon [39].

Adenosine deaminase (ADA, EC 3.5.4.4), an enzyme that metabolises extracellular adenosine, is a ligand of cell surface and soluble CD26 [51–54]. As extracellular adenosine inhibits T-cell proliferation in a dose-dependent manner, it is likely that this inhibition is relieved by the localization of ADA to the cell surface by binding to CD26 [55]. Jurkat cells surface-expressing a mutant of CD26 unable to bind ADA have increased sensitivity to adenosine mediated inhibition of T-cell proliferation [56].

This review discusses the immunological functions and the structure of CD26.

Distribution of expression of cd26

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

Tissue distribution

CD26 is expressed in all organs, primarily on apical surfaces of epithelial and acinar cells and at lower levels on lymphocytes and capillary endothelial cells. Immunohistochemical analysis has detected CD26 in human tissue sections of the gastro-intestinal tract, biliary tract, exocrine pancreas, kidney, uterus, placenta, prostate and epidermis, the adrenal, parotid, sweat, salivary and mammary glands and on endothelia of all organs examined including liver, spleen, lungs and brain [8–10, 57, 58]. Similar studies of rat tissues produced identical data by immunohistochemistry [3, 6, 7, 59] and showed that endothelial cells of capillaries in all organs including lymphoid organs, muscle and brain express CD26 [3]. This immunohistochemical data concords with enzyme cytochemistry using Gly-Pro substrates [60, 61].

Expression on lymphocytes

CD26 is expressed at detectable levels by some resting T cells but the cell-surface expression increases 5–10-fold following stimulation with antigen or anti-CD3 plus interleukin (IL)-2 or with mitogens such as PHA [1, 3, 8, 11, 17, 25, 62–64]. CD26 is expressed on in vivo or in vitro activated CD4+ and CD8+ human T cells [1, 8]. Approximately 56% of CD4+ and 35% of CD8+ cells from peripheral blood lymphocytes [20] and 74–81% of CD4+, and 12–19% of CD8+ PHA activated T lymphocytes [65] express CD26. CD26 is also found on all activated normal human CD3+ T cells and T-cell lines and clones [1, 11]. Cells with a Th1 cytokine profile and phenotype express more CD26 than Th2 clones and its expression is induced by stimuli that favour the development of Th1 responses [66]. The correlation between the CD26 expression and Th1-like immune responses has been suggested to be due to an IL-12-dependent upregulation: IL-12 increases the expression and the DPP IV function of CD26 on phytohemaglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) [67]. In the thymus CD26 is preferentially expressed by medullary thymocytes in humans [68], rats [3] and mice [62], particularly by double negative (CD4CD8) cells [62, 69].

The expression of CD26 on B cells is very low [2, 3], but increases with stimulation by pokeweed mitogen (PWM) or Staphylococcus aureus protein [5, 64]. Approximately 10% of CD16+ NK cells in freshly isolated PBMC have detectable cell surface CD26 [4]. CD26 has been detected on in vitro cultivated CD3+ and CD3 clones of CD4CD8 NK cells regardless of the expression of a T-cell receptor (TCR) complex [2, 54]. Similar to T cells, freshly isolated NK cells express low amounts of CD26, whereas the IL-2 stimulation increases expression [4, 64].

CD26 as a marker of activated, memory and migratory T cells

Both the percentage of cells expressing CD26 and the number of molecules per cell are increased following activation of T cells [54]. The strongest lymphocytic CD26 expression is found on cells coexpressing high densities of other activation markers such as CD25 and CD71 [46, 63] and CD45RO and CD29 [16, 70]. The CD26brightCD4+ population is the CD45RO+CD29+ memory/helper subset which responds to recall antigens, induces B cell immunoglobulin (Ig)G synthesis and activates cytotoxic T cells [25, 46, 71, 72]. Increased cell-surface expression of CD26 has also been reported to be associated with increases in antigen sensitivity, enabling the maintenance of T-cell memory despite decreasing antigen concentration [73]. In addition, resting CD26brightCD4+ memory T cells preferentially undergo transendothelial migration [70, 74].

Costimulation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

CD26 is able to provide a costimulatory signal to T cells [17, 22, 54, 72, 75]. Co-stimulation can be defined as a ‘stimulus necessary for optimal T cell activation delivered jointly to T cells along with the TCR signal’[76]. The costimulatory characteristics of CD26 are that it augments T-cell responses to foreign antigen, initiates signal transduction, increases cytokine secretion and proliferation, upregulates activation markers such as CD25, CD71 and CD69, induces differentiation into effector cells, and enhances provision of help to B cells and cytotoxic T lymphocytes (CTL) [27, 77]. Certain anti-CD26 monoclonal antibodies (MoAbs) induce T cells or CD26 transfected Jurkat cells to increase proliferation and IL-2 production. Moreover, mitogen- and antigen-induced proliferation can be inhibited in vitro by some anti-CD26 antibodies [25, 78]. Cytotoxicity in CTL has been shown to be triggered by antibodies to CD26 [2, 79]. The association of CD26 with other molecules on the cell surface, such as CD45 and ADA, points to mechanisms by which CD26 may mediate signal transduction pathways [52, 80]. CD26 has been shown to induce tyrosine phosphorylation of kinases in these pathways [80–82].

CD26+ cells produce IL-2 regardless of the coexpression of CD4, whereas CD26/CD4 cells produce insignificant amounts of IL-2 [83]. Levels of IL-2 production correlate with CD26 expression in mitogen-stimulated rabbit T cells [65]. Moreover, studies on sorted populations found that the CD26+ subset shows a 2–6-fold greater T-cell proliferation than the CD26 subset in response to tetanus toxoid (TT) [84]. CD26 has been shown to be required for antigen induced proliferation in the absence of exogenous IL-2 [20]. These studies indicate that CD26 is a marker for T cells producing IL-2.

Plana et al. (1991) [85] demonstrated that the anti-CD26 MoAb 134–2C2 increases proliferation of purified T cells either stimulated by phorbol 12-myristate 13-acetate (PMA) at 5 ng/ml or in the presence of exogenous IL-2 (20 U/ml). In addition, the IL-2 secretion is increased, as is the expression of mRNA of IL-2, interferon (IFN)-γ and the IL-2R α and β chains (CD25 and CD122). T-cell proliferation is inhibited when the IL-2R is blocked with an antibody to CD122 in this situation, suggesting that activation via CD26 modifies the IL-2/IL-2R autocrine proliferation pathway [85]. Concordantly, the MoAb CB.1 enhances the IL-2 production by CD4+ and CD8+ T cells in the presence of antigen-presenting cells (APC) and proliferation is inhibited by anti-CD122 [1]. To confirm the role of the autocrine pathway in CD26 mediated T-cell proliferation, Dang et al. have shown that a solid phase immobilized anti-CD26 moAb (1F7) with submitogenic doses of anti-CD3 enhances 3H-thymidine uptake by CD4+ cells [19]. Furthermore, this increase in CD4+ T-cell proliferation was associated with a marked increase in the expression of both IL-2 and IL-2R and proliferation was completely inhibited by an anti-CD122 blocking MoAb. Similar results were obtained when anti-CD2 rather than anti-CD3 was used. CD26 also has a comitogenic effect on CD3 induced IL-2 production by Jurkat cells transfected with cell surface CD26 [81, 86]. In soluble form, the anti-CD26 MoAb 1F7 inhibits T-cell proliferation induced by TT, but in a solid phase immobilized form enhances PMA, CD3 or CD2-mediated proliferation [19, 25]. Similarly, the MoAb AC7 enhances T-cell proliferation stimulated by PMA only in the presence of APC and induces enhanced proliferation only when coimmobilized with anti-CD3 MoAb OKT3 [16]. Anti-CD26 MoAb TA5.9 or Ta1 together with a subthreshold level of anti-CD3 MoAb are able to induce expression of activation markers, such as CD69, CD25 (IL-2R α chain) and CD71 on CD4+ and CD8+ T cells [72]. This is an important indicator of costimulatory ability.

CD26 has a role in the development of effector functions by CD8+ T cells. CD26-triggered cytotoxic activity of CTL requires the presence of Fc receptors on target cells [2]. Anti-CD26 MoAb Ta1 or CB.1 can activate T-cell proliferation and trigger cytotoxicity and granule exocytosis in CTL clones only in the presence of exogenous IL-2 and APC with high density Fc receptors [1, 2, 79]. Others found that cytotoxic activity could be generated in CD8+ T cells costimulated with coimmobilized anti-CD3 and anti-CD26 without APC [72].

The presence of CD26+ T cells enhances the Ig production by human peripheral B cells stimulated with pokeweed mitogen [26], suggesting that CD26 may have a role in potentiating T-helper cell functions. These evidences indicate that CD26 has an extensive range of costimulatory properties. However, such data needs the caveat that antibody cross-linking is a strong signal. Antibody-mediated cross-linking of CD2 generates signals significantly greater than those triggered by its physiological ligands, rat CD48 and human CD58 [87]. Thus, it is possible that MoAbs to CD26 generate signals that are greater than physiological.

TCR signalling

Following cross-linking of the TCR, protein tyrosine kinases (PTKs) such as p59fyn and p56lck are activated. These PTKs phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic domain of ζ chains in the CD3 complex. Phosphorylation allows recruitment of other PTKs, including zeta-associated protein-tyrosine kinase of 70 000 kDa (ZAP-70), to src homology (SH) motifs on CD3. The activated PTKs in turn activate phospholipase C-γ. The subsequent activation of protein kinase C and rise in intracellular Ca2+ concentration initiates a cascade activating Ras and several serine/threonine protein kinases such as mitogen activated protein (MAP) kinase. Following additional signals the transcription of specific genes such as IL-2 is initiated [88]. For example, the signal transduced by CD28 intersects the TCR/CD3 pathway at the level of June kinase [76, 89] which phosphorylates Jun. Phosphorylated June translocates into the nucleus where it contributes to promoting IL-2 gene transcription.

CD26-dependent signal transduction

The mechanism by which signals initiated by CD26 on the cell surface are transduced to the interior of the cell are not fully characterized (Fig. 1). The signalling pathway initiated by CD26 involves intracellular calcium mobilization [86] and precedes increased proliferation [18]. Cross-linking CD26 with anti-CD26 MoAb 1F7 and a secondary antibody also results in increased tyrosine phosphorylation of a variety of proteins known to be substrates of T-cell activation [81]. These proteins are identical to those phosphorylated following cross-linking of anti-CD3 antibodies by a secondary antibody, namely p56lck, p59fyn, ZAP-70, c-Cbl, phospholipase C-γ, and MAP kinase. Thus, CD26 mediated signals involve many of the same substrates as the TCR signal. Inhibition of src PTKs, such as p56lck, by herbimycin A prevents tyrosine phosphorylation of these substrates, further confirming the role of these kinases in CD26 mediated signalling [81].

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Figure 1. A model of CD26/DPP IV action at the T-cell surface. The ADA binding activity of CD26 contributes to the control of adenosine levels at the T-cell surface. Our models of residues 133–766 of CD26/DPP IV (Fig. 2) and of human ADA [90] are depicted here. The peptidase activity of CD26 requires dimerisation [16, 91–93] but the dimerization site is unknown. The CD26-triggered signal transduction pathway is CD3 zeta chain dependent [94] and includes phosphorylation of the PTKs p56(Lck), p59(Fyn) and zeta associated PTK of 70 000 kDa (ZAP-70), and of MAP kinase, Cbl, and phospholipase Cγ[81, 82], suggesting that such signals are transmitted to the nucleus via the TCR/CD3 pathway. The diagrams and models of molecules are not to scale.

Download figure to PowerPoint

There is evidence for a functional relationship between CD26 and the TCR/CD3 complex. Studies of cloned cytotoxic T cells and NK cells have shown that an anti-CD26 MoAb, CB.1, can trigger cytotoxicity in CD3+ cells, but not in CD3 cells [2]. Furthermore, modulation of CD3 leads to transient refractoriness, during which the cells are unresponsive to triggering by anti-CD26 [2]. In contrast, modulation of CD26 enhances T-cell proliferation and does not lead to such refractoriness [18].

Anti-CD3 plus anti-CD26 MoAb 1F7 can modulate the CD3/TCR complex and inhibit the proliferative response of T cells, whereas anti-CD3-mediated T-cell proliferation is increased following CD26 modulation [18]. These findings indicate that cell-surface expression of the TCR/CD3 is required for a CD26 function. However, CD26 is not comodulated with the TCR/CD3 following incubation with anti-CD3 MoAb, indicating that a strong physical linkage between CD26 and TCR/CD3 is unlikely [1, 19]. The ζ chain of CD3 is essential, but not sufficient, for inducing IL-2 production via CD26 [94]. PMA-induced T-cell proliferation is enhanced by anti-CD26 MoAb in the absence of anti-CD3, suggesting the involvement of protein kinase C in the CD26 mediated signal. The link is probably not direct, as anti-CD26 MoAb are not comitogenic with ionomycin [19]. In summary, it may be concluded that while CD26 mediated signalling requires the expression of the TCR and a ζ chain of CD3 and involves many of the same substrates as TCR-mediated signalling, this association is not due to a direct physical connection.

CD26 has been shown to coprecipitate with the 180 kDa isoform of CD45. This isoform is expressed preferentially on CD45RO+‘memory’cells, corresponding with the distribution of CD26 [80]. An interaction between CD26 and CD45 could account for increases in activity of PTKs, phosphorylation of CD3 and calcium mobilization following anti-CD26 modulation.

These findings provide evidence that the signal transduced by CD26 overlaps with the TCR/CD3 pathway. Both the TCR/CD3 and CD26 mediated signals result in activation and translocation of the transcription factor NF-κB [95]. Such observations support a costimulatory role for CD26 in CD3 induced signal transduction.

The role of DPP IV activity in T-cell activation

CD26 has a DPP IV ecto-peptidase activity that catalyses the cleavage of N-terminal dipeptides from polypeptides with proline or, in order of decreasing efficiency, alanine, hydroxyproline, serine, glycine, valine or leucine at the second position from the amino terminus [30, 31, 37, 96]. Many natural substrates are known, including chemokines, neuropeptides, hormones and growth factors, whose activity is modulated by the cleavage [31, 36, 96–100]. Such cleavage generally results in the inactivation of biological activity and contributes to the regulatory mechanisms of many biological processes. Indeed, using CD26-deficient rodents it has been shown that the DPP IV activity is clearly important for digestion [101] and the control of blood glucose concentration [102]. In addition, there is a clear role for DPP IV activity in T cell and monocyte migration [38, 70, 74, 103].

The importance of the DPP IV activity of CD26 in vivo is debated because inhibitor specificity is difficult to guarantee [10, 99]. Studies employing DPP IV enzyme inhibitors show that they inhibit T-cell proliferation and cytokine production [22, 24, 29, 104–107]. Studying both mitogen and antigen induced T-cell activation in vitro, it has been found that inhibitors of DPP IV impair DNA synthesis, Ig production and secretion, and production of IL-2 and IFN-γ[105]. Similar results were observed in PWM-stimulated PBMC and U937-H cells, including a reduction in IL-6 and IL-1β production [24, 107]. In addition, competitive DPP IV inhibitors impair DNA synthesis in B cells [5] and downregulate proliferation, but not cytotoxicity, of IL-2 stimulated CD56+ NK cells. DPP IV inhibitors have been shown to suppress phosphorylation of p56lck, Ca2+ flux and activation of phosphoinositol-3 and the MAP kinases ERK1 and ERK2 [82], all known to be involved in T-cell activation. However, tyrosine phosphorylation of proteins that are unaffected by CD26-triggering, such as MAP kinase p38, are also induced by DPP IV inhibitors [64]. Reinhold et al. (1997) have demonstrated that DPP IV inhibitors induce secretion of the inhibitory cytokine transforming growth factor-β1 in PWM-stimulated PBMC [108]. These results, however, do not exclude effects of DPP IV inhibitors unrelated to their inhibition of the DPP IV activity of CD26 [54].

Many studies do not support a role for the DPP IV activity in in vitro assays of CD26 function. CD26-mediated triggering of cytotoxicity of activated T cells is not inhibited by ‘highly specific’ competitive and irreversible inhibitors [109]. Both CD26+ and CD26 Jurkat cells have been found to be equally susceptible to the effects of DPP IV inhibition, indicating that suppression of T cell activation by DPP IV inhibitors could be due to effects on non-DPP IV enzymatic activities [77]. The CD26/DPP IV deficient rat strain (DPP IV-negative Fischer344) exhibits no defects in in vitro responses to mitogen or antigen [110]. Moreover, suppression of in vitro responses to mitogens or Mycobacterium tuberculosis antigen by the DPP IV inhibitor Lys(Z(NO2))-thiazolidide is equally effective in wild type and CD26-deficient Fischer344 rat cells [111]. Interestingly, PBMC and kidney from CD26-deficient Fischer344 rats exhibit 50 and 1%, respectively, of the Ala-Pro hydrolysing (DPP IV-like) enzyme activity of wild-type Fischer344 rats [92], indicating that leucocytes possess important DPP IV-like enzyme activity(ies).

An approach to resolving conflicting results obtained with enzyme inhibitors is to produce mutant CD26 lacking DPP IV activity by mutating the active site serine. Most of 11 mutant enzyme-negative CD26 expressing TCR+ Jurkat clones were more easily triggered via CD26 than Jurkat cells transfected with wild-type CD26 [112]. In a separate study, a Jurkat cell line that surface expressed DPP IV-negative CD26 produced significantly more IL-2 than untransfected but less than wild-type CD26 transfected cells, suggesting that DPP IV activity accounts for only some of the IL-2 inducing activity of CD26 [22, 27]. Most importantly, the costimulatory activity of CD26 is retained in mutants lacking most of the hydrolase domain [113]. These data indicate that proteolytic activity is not a prerequisite for the T-cell activating or costimulating properties of CD26 in vitro.

Adenosine deaminase as a ligand of cd26

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

CD26 binds to ADA [51–53]. This was verified by partial sequencing of a 43-kDa band that coprecipitates with CD26. Both the percentages of cells expressing ADA and CD26 and the numbers of both molecules per cell are increased when T cells are activated via the TCR/CD3 complex [54]. ADA binds human CD26 with KA of 4–20 nm[114]. The enzyme activities of ADA and CD26 are unaffected by their binding, indicating that this binding is independent of the catalytic functions of both enzymes [53, 55, 64]. ADA bound to CD26 has an enzymatic role in protecting T cells from an adenosine-mediated inhibition of proliferation [53, 55, 56, 115]. In addition, ADA has been proposed to have a catalytically independent function as a costimulatory molecule [54, 116]. The association of ADA with CD26 is importantly involved in the ability of CD26 to promote proliferation and cytokine production.

Adenosine deaminase

ADA is a soluble globular enzyme present in all mammalian tissues that plays an important role in development and function of lymphoid tissue [117–119]. The main consequence of hereditary deficiency of ADA is severe combined immune deficiency, a profound lymphopenia causing impairment of cellular and humoral immunity. The mechanism is probably an accumulation of toxic metabolites [55]. ADA catalyses the irreversible deamination of adenosine to inosine and of 2-deoxyadenosine to 2-deoxyinosine. ADA deficiencies are associated with high adenosine levels [116]. ADA deficiency is also associated with hepatic, skeletal and neurologic abnormalities in some patients while ADA knockout mice die perinatally of hepatic and pulmonary injury [120–122].

Although ADA is more than 90% intracellular [123], it is also located on the cell surface of T and B lymphocytes [124]. ADA in humans was thought to have two forms, ADA-long and ADA-short, until ADA-long was found to be a complex of a dimeric ADA binding protein (ADAbp) with two molecules of ADA running at 220 kDa on SDS-PAGE [125]. ADAbp was shown to be CD26 [51–53]. ADA binds both monomeric and dimeric forms of CD26 [123](Fig. 1).

The first full drafts of the human genome have shown that the most dramatic difference between human and nonmammalian genomes is the greater frequency of functional domains and the occurrence of novel functional domains in human proteins [126]. This implies that complexity arose from the accumulation of additional functions in proteins. ADA binding by human CD26 is such an additional function in that CD26 has analogues in all species examined but only in higher mammals does CD26 bind ADA. ADA binds to CD26 in humans, cattle and rabbits but not in rats or mice [55, 59, 90, 114, 127, 128]. The inability of ADA of any species to bind mouse or rat CD26 and our observations of differences in surface phobicity and charge between mouse and human CD26 and ADA [90] suggest that ADA and CD26 coevolved their ability to interact. The selective advantage of this interaction is probably additional control over cell surface concentrations of inhibitory purines. CD73 (ecto-5′ nucleotidase), CD38 and CD39 also contribute to extracellular purine metabolism [129–132]. The interesting observation that cell surface CD26 is not normally and not readily saturated with ADA [51, 54, 55, 72, 90] is consistent with a regulatory role for ADA-CD26 binding.

Dong et al. (1996) found that ADA and CD26 colocalise only on the cell surface and not inside the cell, suggesting that ADA is not transported through the cell membrane by CD26. Also, ADA is detected on murine B cells transfected with human CD26 when cocultured with human cells as the only source of human ADA, indicating that cell surface ADA can be acquired from ADA secreted by other cells [55].

A costimulatory, extra-enzymatic role of ecto-ADA?

It is likely that the signal transduced by CD26 is initiated by a ligand binding event [80]. As discussed below, ADA has an important enzymatic role in relieving adenosine-mediated inhibition of proliferation but several observations point to an additional extra-enzymatic role for CD26 associated ADA. Firstly, exogenous ADA can enhance proliferation of CD4+ cells induced by anti-CD3 even in the presence of ADA inhibitors, indicating an enzyme-independent mechanism of ADA action [54]. Secondly, incubation of T cells with exogenous ADA enhances the increase in intracellular Ca2+ induced by anti-CD3 MoAb, indicating that ADA initiates signalling events [116]. However, the enhancement was modest, and possibly not significant. Thirdly, the anti-CD26 MoAbs TA5.9, AC7, 134–2C2 and 22C3, that block ADA binding, costimulate anti-CD3 dependent T-cell proliferation [16, 28, 72, 85] suggesting that ligation of the ADA binding site on CD26 may be sufficient to trigger a signal. However, this should be confirmed using Fab fragments of these MoAbs to control for a cross-linking effect. Moreover, the MoAb 5F8 inhibits ADA binding but has no effect on T cells [133]. Anti-CD26 MoAb to other epitopes can costimulate T cells and they may do so by other mechanisms.

Perhaps the greater lethality seen in ADA knockout mice than in humans whose ADA lacks catalytic activity is owing to the retained ability of the catalytically inert human ADA to trigger CD26. A healthy Ethiopian bearing a mutation that prevents his ADA from binding to CD26 has been observed [134] and it would be interesting to examine his T-cell responses. A human bearing the possibly more lethal double mutation in ADA such that it lacks both catalytic and CD26 binding activities has not been observed. In summary, the proposition that ADA binding to CD26 has an extra-enzymatic role is controversial.

Role of ADA as ecto-enzyme

Several lines of evidence indicate that ADA bound to cell surface CD26 functions to increase T-cell proliferation. Inhibition of ADA by deoxycoformycin represses early events in T-cell activation and interferes with allogeneic and lectin-induced proliferation of activated T cells, particularly the production of IL-2 and the expression of the IL-2 receptor [115]. In contrast to Martin et al. [54], Dong et al. found that exogenous ADA influences the proliferation of purified T cells only in the presence of adenosine, and that this effect is potentiated when ADA enzyme activity is inhibited by deoxycoformycin [55]. Adenosine inhibits proliferation of purified T cells stimulated with immobilized anti-CD3. This inhibition is dose dependent (100% in 1 mm adenosine) and is relieved by the addition of exogenous ADA at 10 ng/ml. This effect persists after free ADA is removed, suggesting that cell surface ADA may be sufficient to deaminate adenosine. This is supported by the finding that CD26 transfected Jurkat cells, which coexpress CD26 and ADA on their surface, are more resistant to the inhibitory effects of adenosine, than are CD26 Jurkat cells. Moreover, when the proliferation and the IL-2 production are induced by anti-CD3 MoAb plus PMA, the resistance to inhibition by adenosine correlates with levels of cell surface, but not intracellular, ADA [27, 55]. Furthermore, Jurkat cells transfected with a mutant cell surface CD26 unable to bind ADA are less resistant to the inhibitory effect of adenosine on the production of IL-2 than are wild-type CD26 expressing Jurkat cells [56]. Thus, the enhancing effect of ADA binding to human T cells via CD26 is well established but the mechanism(s) of action requires clarification.

Extracellular matrix (ecm) interactions with cd26

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

A functional interaction between CD26 and ECM has been indicated by in vitro experiments in which the migratory behaviours of T cells or hepatocytes are enhanced by the presence of CD26 and collagen and/or fibronectin [135–137]. β-propeller structures, including the 4-blade β-propeller of matrix metalloproteinases, are commonly involved in multiple protein–protein interactions [138, 139] so the β-propeller domain of CD26 probably has several ligands. Indeed, using fragments of CD26, the binding sites of fibronectin [140, 141] and collagen [142] on rat CD26 have been localized to the β-propeller domain of CD26 in the regions 313–319 (LQWLRRI) and 236–491, respectively. Interestingly, using immunoblotting [143] and srhCD26 [35, 144] we have been unable to demonstrate collagen binding to human CD26 [10]. Perhaps the association of CD26 with collagen is indirect. Integrins are candidate linker molecules for indirect interaction between CD26 and ECM because the integrin α3β1 is a ligand of fibroblast activation protein (FAP/seprase) [145]. FAP is very similar to CD26 and the two genes exhibit 63% identity and are less than 100 kb apart on chromosome 2 [146], suggesting a gene duplication (for a detailed comparison see [10]). Both recombinant and natural FAP have gelatinase activity [147] and gelatinases generally bind to an integrin. However, despite its close similarity to FAP, human CD26 lacks gelatinase activity. We have investigated this question using both gelatin zymograms [147] and fluorescein-conjugated gelatin (Fig. 3)as substrates and expression of human CD26 and FAP using several expression constructs in the vectors pEE14 [90, 147] and pcDNA3.1 [148]. Reports of collagenase or gelatinase activity by CD26 [93] perhaps indicate species differences or contaminating molecules in CD26 prepared from natural sources [149].

image

Figure 3. Gelatinase activity of CD26 gene family resides only in FAP.DPP8, a recently cloned DPP IV-like enzyme [148], FAP [168] and CD26 [86] were expressed using the pcDNA3.1 vector. Gelatinase activity of 100 000 transfected COS-7 cells was measured using fluorescein conjugated gelatin (Molecular Probes, Portland OR, USA) at 100 µg/ml (M. Obradovic, C. Abbott & M. Gorrell, unpublished observations).

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Structure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

Structure of CD26

The structure of CD26 is unique amongst leucocyte surface molecules. CD26 is a member of the POP gene family [33], whose members have an α/β hydrolase domain and a seven-blade β-propeller domain [34, 152]. CD26 is the only POP family member expressed on leucocytes. Few other leucocyte surface antigens include a seven-blade β-propeller domain, the best known being integrin α chain, which was modelled on the G protein β chain [153]. Surprisingly, both ends of the polypeptide contribute to the α/β hydrolase domain of POP. These two segments of POP align with residues 29–132 and 502–766 of human CD26 [90, 152]. As CD26 is a type II protein, this causes the propeller domain, formed by residues 133–500 in our model of the tertiary structure, to point its lower face toward the extracellular milieu. The upper face of the propeller domain is covalently joined to the α/β hydrolase domain such that the catalytic cleft lies within an enclosed cavity that has its narrow opening in the propeller lower face (Fig. 2A). A unique feature of the β-propeller domain of the POP family is its flexibility. Other propellers are rigid owing to a covalent link or disulfide bond between their first and last blades but POP has only hydrophobic bonds and salt bridges in this location and the first and last blades probably open to allow substrate entry [151, 154]. The propeller opening, which is about 20 Angstroms from the catalytic serine, is only about 4 Angstroms across but the diameter of peptide substrates is greater than 6 Angstroms. Therefore, controlling access by substrates to the catalytic site likely involves controlling the opening of this central pore in the lower face of the β propeller. Evidence for this idea is that residues that line the central pore of CD26 are highly conserved [150] and catalytic activity is ablated by a point mutation that either alters the charge of a residue that lines the central pore of CD26 [150] or creates a disulfide bond between the first and last blades of the β-propeller of POP [151]. We propose that mutations of pore-lining residues ablate catalysis by interfering with the ability of the central pore to dilate.

image

Figure 2. A prediction of CD26 structure. (A) Structure prediction of residues 133–766 of human CD26. Ribbon diagram of the N-terminal portion of the hydrolase domain (residues 502–766) and the predicted β-propeller domain (residues 133–501), coloured blue to red. It is likely that the remainder of the α/β hydrolase domain is formed by about 100 residues that are immediately N-terminal to Asp133. The transmembrane domain (residues 7–28) is anticipated to be above the hydrolase domain in this view. Substrate access to the catalytic site is probably via the central opening in the lower face of the propeller [150, 151]. The ADA binding region is on the left side of the lower face [90]. Approximate predicted locations of the catalytic serine (S) and of potentially glycosylated asparagines (N) are indicated. (B) A space-filled model of residues 133–501, with surface charge depicted as red (negative) and blue (positive), viewed towards the lower face. Propeller blades are numbered 1 to 7. The hydrophobic residues Leu294 and Val341 are essential for ADA binding. The positively charged residues Arg343 and Lys441 are important in epitopes of antibodies that inhibit ADA binding [90]. The Glu205 is essential for enzyme activity [150]. Figures prepared using MOLSCRIPT (A), Delphi (B) and Canvas versus 5.03 (M. Gorrell & W.B. Church, unpublished observations).

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CD26 is a 110-kDa glycoprotein which is only catalytically active as a dimer [16, 92, 93, 123]. The relative molecular mass of the dimer is 220–264 kDa by gel filtration but surprisingly 140–160 kDa when estimated by SDS-PAGE [3, 16, 91, 123, 125, 155]. The pI of glycosylation isoforms ranges from 3.5 to 5.9 [156]. The CD26 protein is well conserved between species. Human CD26 [157] shows 85% identity to rat CD26 and 36% identity with yeast dipeptidyl aminopeptidase B [158]. The human CD26 gene consists of 26 exons on the long arm of chromosome 2 [159]. Recent analyses show that this gene is at 2q24.2 and covers 81 810 bases beginning at base 163 763 760 on chromosome 2 and separated from the 72 847 bp FAP gene by only 96 632 bases [146]. The nucleotide sequence of the 3.4 kb human CD26 cDNA predicts a protein of 766 amino acids, with six amino acids in the cytoplasmic region and a 22 residue hydrophobic transmembrane domain [86, 157] forming a characteristic signal sequence [160, 161]. CD26 contains nine potential N-linked glycosylation sites [157] which in our model primarily lie on and presumably shield outer loops at the interface between the two domains of CD26 [90](Fig. 2A).

The sequence around the predicted catalytic serine, GlyTrpSerTyrGly (G-W-S-Y-G), fits the serine proteinase consensus motif G-x-S-x-G [86]. Mutation of Ser624, Asp702 or His734 of mouse CD26 abolishes the catalytic activity while retaining normal surface expression and biochemical properties [162]. CD26 is an atypical serine proteinase as the arrangement of these amino acids (nucleophile (serine)-acid-histidine) is the reverse of the ‘histidine-acid-nucleophile’ pattern seen in classical serine proteinases. In addition, in CD26 this catalytic consensus sequence is split between two exons, differing from the classical serine proteinases in which this sequence occurs within a single exon [159].

The adenosine deaminase binding site on CD26

ADA binding is blocked by certain anti-CD26 MoAb (TA5.9, 134–2C2, 22C3, AC7, S23, 5F8 and 2F9) that define a similar epitope, suggesting that ADA binds to a single site on CD26 [28, 53, 90, 163–165]. The inability of rat CD26 to bind ADA [59, 90, 127, 163] implicates residues that are nonconserved between rat and human CD26 in the ADA binding site. Dong et al. sequentially employed CD26 deletion, human-rat swap and point mutations to identify that the region Leu340 to Arg343 is essential for ADA binding to CD26 [56]. Abbott et al. mutated individual nonconserved, hydrophobic residues of CD26 and determined that Leu294 and Val341 are required but not sufficient for the ADA binding, as these two residues do not confer ADA binding activity upon rat CD26 [90]. Sites of protein–protein interaction involve both charge and hydrophobic interactions [166]. Concordantly, two hydrophobic sites on CD26 [90] and one charged residue on ADA, Arg142 [134], have been identified as essential for the ADA-CD26 binding. Thus, additional unidentified residues on CD26 are essential for the ADA binding and one such residue is probably acidic and forms a salt bridge with Arg142 of ADA.

The crystal structure of POP [154] has been used to model the extracellular portion of CD26 [10, 90]. POP has two domains: an α/β hydrolase catalytic domain, and a seven-blade β-propeller domain formed by repeated four-stranded β sheets of about 50 residues each. CD26 and POP have a 21% amino acid identity in the C-terminal region [90], indicating that this region of CD26 forms an α/β hydrolase fold. Although the β-propeller domain of POP shows only 15% sequence identity with CD26, an automated alignment was obtained and the predicted structural homologues of CD26 residues 100–500 included β-propellers [90]. Furthermore, FTIR and CD spectrometry of CD26 show that POP and CD26 have very similar compositions of secondary structure [15, 167]. Therefore, it is likely that the overall topologies of POP and CD26 are similar. Two residues required for ADA binding, Leu294 and Val341, are in loops between the 3rd and 4th strands on the outside rim of the lower face of the predicted β-propeller domain of CD26 (Fig. 2B). This location allows the ADA binding to avoid blocking the propeller opening [10, 90, 152].

Soluble cd26

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

Origin and characteristics of soluble CD26

Since DPP IV activity was first detected in serum about 25 years ago [169, 170] considerable understanding of the nature, origin and activities of serum DPP IV has been achieved. Initially, serum CD26 was detected by DPP IV enzyme activity, later by immunoreactivity [13] and now by ADA binding [14, 15, 171]. ADA binding assays are clearly specific for CD26 and show that at least 90% of the serum DPP IV activity is derived from CD26 [15]. Serum CD26 is 110 kDa, similar to cell surface CD26 [14, 15, 172]. It is soluble because it lacks the transmembrane domain [161, 173], which ends 28 residues from the N-terminus. The naturally occurring soluble form of CD26 starts at Ser39 of human serum CD26 [14, 15, 167] and the corresponding serine in sheep [174] and pig [175, 176] kidney CD26. Other natural and recombinant forms of sCD26 are similar. The N-terminus of purified CD26 from rat liver and kidney is Leu29 [7] and from human seminal plasma [167] or cell culture supernatants of transfected cell lines [15, 29] is Asn30.

Analysis of CD26 deficient (–/–) mice has shown that the predominant DPP IV (Gly-Pro hydrolysis) activity in mouse serum is CD26 derived [102] but significant levels of DPP IV-like (Ala-Pro hydrolysis) activity of unknown origin occur in the CD26-deficient Fischer 344 rat and CD26-/- mouse strains [92] (Gorrell, Abbott & Marguet, unpublished observations). Moreover, serum of the CD26-deficient Fischer 344 rat contains detectable Gly-Pro hydrolysing activity [177]. CD26 mRNA expression can occur in the absence of detectable CD26 protein and Northern blot has detected little regulation of CD26 mRNA [13, 64, 149, 159, 178] (Ong, Yu, Abbott & Gorrell, unpublished observations). However, variations in the CD26 mRNA expression are detectable by gene array [179–181] (Shackel, Gorrell & McCaughan, unpublished observations). About 40–50% of T cells in human blood express cell surface CD26 [11, 64] but most or all human T cells contain CD26 mRNA and CD26 protein that is surface expressed 4–8 h after stimulation [18, 156, 178]. Pulse chase experiments [182, 183] and transfection [163] found that sCD26 derives from cell surface CD26. The mechanism of shedding sCD26 from the cell surface is unknown but is thought to be proteolytic.

The level of CD26 in serum from healthy adults is about 22 nmol p-nitroanilide/min/ml, which corresponds to about 7 µg/ml [13, 29, 184]. The cellular origin(s) of the serum CD26 is unclear. It may derive from all CD26 expressing cells that contact blood. Serum CD26 levels generally decrease in disease unless a liver injury or extensive lymphocyte proliferation is involved (Table 1). The 10-fold increase in serum CD26 during liver regeneration could not be explained by an increased expression in the liver [13]. Hepatocytes exhibit aberrant basolateral domain CD26 expression in injured liver [60]. Thus, perhaps the injured liver releases more hepatocyte derived CD26 into blood rather than bile. Changes in the serum CD26 levels in other conditions might reflect changes in levels released by lymphocytes. Serum CD26 may help inactivate and thereby prevent systemic effects from bioactive peptides following their local production.

Table 1.  Serum DPP IV in diseases
Effect and disease/conditionReferences
Increased
Liver regeneration (rat)[13]
Lymphocytic leukemia, Hodgkin's lymphoma[185]
Hepatic dysfunction (human)[186]
Cancer of bile duct or pancreas (human)[187]
Hepatoma (human, rat, chicken)[187–189]
Kidney transplant rejection (rat)[190]
MRL/l mouse[191]
Encephalitis (EAE; SJL mouse)[192]
Osteoporosis (human)[193]
Reduced
Oral squamous cell carcinoma (human)[186]
Major depression[12, 194]
Rheumatoid arthritis (human, mouse)[195–197]
SLE (human, NZB mouse)[196, 198]
HIV (Also, serum ADA is increased)[44, 199]
Anorexia nervosa, bulimia nervosa[200]
Diabetes mellitus and hypertension (human)[187]
Gastrointestinal cancer, nonhepatic[187]
Immunosuppression (rat)[190]
Pregnancy (human)[12, 201]
Women less than men[201]
Neonates less than adults[185]
No change
Myelocytic leukemia (human)[185]

Function of soluble CD26

The functions of sCD26 have been studied using both natural and recombinant forms. srhCD26 has been made by deletion of nucleotides coding for residues in the signal/transmembrane domain [14, 15, 29] or a single amino acid point mutation at Leu28 [35, 144]. The findings are consistent with an immunoregulatory role for sCD26 in vivo, both locally and within the systemic circulation. Exogenous srhCD26 is not itself mitogenic but is able to enhance proliferation of activated peripheral blood lymphocytes [29, 202]. This augmentation occurred only in association with a recall antigen TT but not when the proliferation was induced by PHA or anti-CD3 [29]. Proliferation was increased by srhCD26 1.5–5 times in PBMC from 50% of subjects that positively responded to TT and in cultures of a TT-specific T-cell clone. Concentrations of srhCD26 greater than the optimum (0.5 µg/ml) diminished this effect. In addition, natural sCD26 has been shown to enhance proliferation (1.4–2.6-fold) of PBMC that respond weakly but not PBMC that respond vigorously to Candida or TT [202]. Moreover, PBMC from HIV+ individuals have been examined. Proliferation of PBMC that respond weakly to Candida was dramatically enhanced by preincubation with sCD26 (10–117-fold), whereas strong responses to Candida were only modestly enhanced (1.1–3.5-fold) or inhibited (0.3–0.8-fold) [202]. We have obtained concordant data using Herpes simplex virus as the recall antigen but found that srhCD26 also demonstrates an enhancement effect on PBMCs suboptimally stimulated with PHA or anti-CD3 [10]. Thus, sCD26 exerts regulatory effects on in vitro T-cell memory responses decreasing strong responses and increasing weak responses.

The mechanism by which sCD26 influences T-cell proliferation is unclear. Experiments in which srhCD26 was preincubated with diisopropyl fluorophosphate (DFP), a serine proteinase inhibitor, suggest that catalysis has an important role [29]. However, the contribution of the catalytic activity of CD26 to stimulating T-cell proliferation is controversial (see above; the ‘role of DPP IV activity’). Using srhCD26 rendered catalytically inert by single amino acid point mutation in such experiments may be more informative. Furthermore, the potent stimulation of T-cell proliferation by ADA, dependent upon its binding to cell surface CD26 [56], suggests that sCD26 should decoy away ADA and thereby inhibit T-cell proliferation, rather than enhance it as has been observed [29, 202]. This paradox, which may be caused by opposing activities, such as catalysis and ligand decoy effects, requires further study. The costimulatory molecule CD28 has both activating and inhibitory ligands. Similarly, the CD26 data is consistent with the existence of an unidentified inhibitory ligand of CD26.

Chemokines and other natural substrates

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

Neuropeptide Y is the most readily hydrolysed natural substrate of DPP IV/CD26 [31]. Its importance is its potential role in the control of appetite (reviewed in [99]). Natural substrates currently attracting interest include glucagon, glucagon-like peptide (GLP)-1 and GLP-2 owing to the differential effects of intact and DPP IV truncated glucagon and GLP in influencing enterocyte proliferation, blood glucose concentration and insulin production [96, 97, 102, 203–205].

Since Oravecz and colleagues first discovered that the receptor specificity of CCL5 is altered by DPP IV hydrolysis [35], the aspect of CD26 biology of greatest interest to immunologists has been the ability of DPP IV/CD26 to inactivate or alter the specificity of an increasing number of chemokines. CCL3 (macrophage inflammatory protein-1α isoform LD78β), CCL4 (macrophage inflammatory protein-1β), CCL5, CCL11 (eotaxin), CCL22 (monocyte derived chemokine), CXCL9 (HuMlG, monokine induced by IFN-γ), CXCL10 (inflammatory protein-10), CXCL11 (IFN-inducible T cell α chemoattractant) and CXCL12 are DPP IV substrates in their natural in vivo form [35, 38, 48, 49, 100, 103, 206–209]. CCL3, CCL5, CCL11, CCL22 and CXCL12, but not CXCL6 or CXCL10, exhibit altered chemotactic activity following DPP IV-mediated truncation [35, 38, 49]. Notably, the chemokines CXCL2, CCL2 and CCL7 have penultimate prolines but are not hydrolyzed by DPP IV [35, 210]. Detailed discussions appear in recent reviews [10, 37, 39, 99]. CD26 is preferentially expressed by Th1 cells [66, 181, 211] and DPP IV-mediated chemokine cleavage potentially contributes to the downregulation of Th2 responses by Th1 cells [10] and increases the chemoattraction of monocytes via hydrolysis of CXCL12 [49] and CCL3 [38].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References

The regulation of leucocyte trafficking involves numerous proteinases, chemokines and adhesion molecules. CD26 is a dipeptidyl aminopeptidase that modifies activities of chemokines and interacts with ECM. In particular, this peptidase tends to enhance the chemoattraction of monocytes and diminish stimulation of Th2 type chemokine receptors.

CD26 is a costimulatory molecule in that CD26 MoAb can trigger an activation cascade, including proliferation, cytokine production and activation marker expression, via phosphorylation of substrates that overlap with those involved in TCR/CD3 or TCR/CD2 induced signalling. Expression of the TCR is obligatory for CD26 mediated signals. Thus, CD26 differs from CD28, which triggers a separate signal transduction pathway with no TCR requirement. The CD26 pathway predominantly stimulates preactivated cells suggesting that CD26 is not essential for initial activation. Rather, it may provide an additional activating signal, augmenting the response of CD3+ cells already participating in an immune reaction or recently activated.

The triggering mechanism for the costimulatory activity of CD26 is unclear. CD26 unequivocally has ADA binding and peptidase activities. Some controversy surrounds the relative contributions of these activities to stimulating T-cell proliferation. ADA binding to CD26 on the surface of T cells clearly increases proliferation. The underlying mechanism primarily involves enhanced metabolism of inhibitory adenosine but may also involve signalling. Recent improvements in understanding the structure of CD26 and the discovery of single amino acid point mutations that ablate ADA binding is assisting in resolving this question and questions regarding the function of soluble CD26. Soluble CD26 is at significant levels in serum, the levels alter in many diseases and soluble CD26 can modulate in vitro T-cell proliferation, so an improved appreciation of its functions is desirable. CD26 is an activation marker on B and NK cells and the functioning of CD26 on these cells deserves renewed attention.

The characteristics of CD26 and its unique structure amongst lymphocyte surface molecules mean that intense study should lead to new insights into the regulation of lymphocyte stimulation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distribution of expression of cd26
  5. Costimulation
  6. Adenosine deaminase as a ligand of cd26
  7. Extracellular matrix (ecm) interactions with cd26
  8. Structure
  9. Soluble cd26
  10. Chemokines and other natural substrates
  11. Conclusion
  12. Acknowledgments
  13. References
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    Proost P, Menten P, Struyf S, Schutyser E, De Meester I, Van Damme J. Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78 beta into a most efficient monocyte attractant and CCR1 agonist. Blood 2000; 96:167480.
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