An excellent overview of the biology of CD26/DPP-4 and its actions in the immune system with a focus on chemokines is found in Immunology Today 1999 20:367-375. Originally identified as a lymphocyte cell surface ADA binding protein with co-stimulatory activity, CD26 expression and activity are increased following T cell activation, and distinct subpopulations of CD26bright T cells have been identified that subserve multiple functions including antigen recall, immunoglobulin synthesis, and activation of cytotoxic T cells CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol. 2001 Sep;54(3):249-64. Review.

CD26 associates with other lymphocyte cell surface molecules including the chemokine receptor CXCR4, ADA and CD45, and monoclonal antibodies against CD26 promote aggregation of both CD26 and CD45 into lymphocyte lipid rafts CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12138-43.. Furthermore, CD26 directly binds to the cytoplasmic domain of CD45, providing a mechanism for engagement of specific signal transduction pathways leading to interleukin-2 production, a common downstream event secondary to CD26 activation . 

Conversely, interleukin induces CD26 expression on a subset of human natural killer lymhocytes. Activation of lymphocyte CD26 leads to increases in intracellular calcium, tyrosine phosphorylation of multiple substrates, and cell proliferation. CD26 undergoes mannose-6 phosphorylation leading to interaction with the mannose 6- phosphate/insulin-like growth factor II receptor (M6P/IGFII) receptor following T cell activation. Soluble CD26 also interacts with the (M6P/IGFII) and enhances transendothelial T cell migration, an effect that requires its DPP-IV enzymatic activity Soluble CD26/dipeptidyl peptidase IV enhances transendothelial migration via its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cell Immunol. 2002 Jan;215(1):106-10.

What is the role of the catalytic domain of CD26 in the regulation of immune function? One approach to this issue involves the use of selective versus non-selective DPP-4 inhibitors for analysis of preclinical toxicity and effects on immune function. Lankas and colleagues examined the preclinical toxicity and effects on human T cells of a panel of selective (for DPP-4) vs. non-selective (cross-react against DPP-8/9, and QPP) inhibitors. Studies carried out in dogs demonstrated gastrointestinal toxicity of the DPP-8/9 inhibitors. Similarly, DPP-8/9 selective inhibitors produce considerable multi-system toxicity in rats and mice, resulting in mortality. The QPP-selective inhibitor produced reticulocytopneia in rats. Inhibitors of DPP-8/9, but not inhibitors of DPP-4, impaired human mononuclear cell proliferation following mitogen stimulation. See  Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005 Oct;54(10):2988-94

The biological role(s)  of DPP-8 and DPP-9 have not been extensively studied but they appear to exhibit enzymatic activity that overlaps with that described for DPP-4. Both enzymes cleave  glucagon-like peptide-1, glucagon-like peptide-2, neuropeptide Y and peptide YY, but with marked kinetic differences compared to dipeptidyl peptidase-4, as described in Dipeptidyl peptidase 8 and 9 specificity and molecular characterization compared to dipeptidyl peptidase IV. Biochem J. 2006 Feb 13; [Epub ahead of print]

A link between CD26 expression/activity and levels of the proinflammatory chemokine stromal cell-derived factor-1 (SDF-1) was established in studies of experimental arthritis in mice, and observational studies in human subjects with rheumatoid arthritis. CD26-/- mice exhibited comparatively greater degrees of experimental joint inflammation following induction of antigen-induced arthritis, but no major differences in the basal humoral or cellular immune response were detected in CD26-/- vs control mice with AIA. However T cell activation led to increased interferon-g production in lymph node supernatants from CD26-/- mice. The cleavage of the chemokine SDF-1 was modulated by CD26 activity both in vitro, and in vivo. Intriguingly, the expression of the receptor for SDF-1, CXCR-4, was increased in CD26-/- joint tissue. These findings raise the possibility that CD26 expression may modify the activity of experimental inflammation in part through changing the levels of chemokines with inflammatory activity. See Circulating CD26 Is Negatively Associated with Inflammation in Human and Experimental Arthritis. Am J Pathol. 2005 Feb;166(2):433-442

The majority of ex p eriments assessing lym p hocyte CD26 activity use s p ecific antibodies for CD26 activation; whether the enzymatic p e p tidase activity of CD26 is involved in or required for multi p le as p ects of lym p hocyte signaling has not always been conclusively determined as reviewed in CD26: an expanding role in immune regulation and cancer. Histol Histopathol. 2002 Oct;17(4):1213-26

Ex p eriments carried out with mutant soluble CD26 molecules have demonstrated the im p ortance of DPP-IV enzymatic activity for enhancement of T cell p roliferation and induction of monocyte CD86 ex p ression Soluble CD26/dipeptidyl peptidase IV induces T cell proliferation through CD86 up-regulation on APCs. J Immunol. 2001 Dec 15;167(12):6745-55 t;/MDL></Cite></EndNote> .

Similarly, anti-CD26 monoclonal antibodies inhibit T cell growth and p roliferation via induction of G1/S arrest, effects which is also de p endent on the enzymatic function of CD26 G1/S cell cycle arrest provoked in human T cells by antibody to CD26. Immunology. 2002 Nov;107(3):325-33.

Inter p retation of data obtained from ex p eriments using s p ecific DPP-4 inhibitors to examine lym p hocyte function is com p licated by the s p ecificity of the inhibitor em p loyed, however DPP-4 inhibition has been shown to modify T and β cell p roliferation, and cytokine p roduction, as reviewed in CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol. 2001 Sep;54(3):249-64. Review.

In contrast, analyses of cells from the CD26/DPP-4 mutant Fischer 344 rat In vitro immune responsiveness of rats lacking active dipeptidylpeptidase IV. Cell Immunol. 1994 Oct 15;158(2):269-80 or the CD26/DPP-IV knockout mouse have not yet revealed major defects in lym p hocyte activation or immune function. 

However, the Fischer 344 mutant rat does exhibit defects in T cell subsets in response to immunization, or in the setting of experimental asthma. The number of CD4(+) T lymphocytes was markedly reduced compared to wild-type F344 and the decrease in T cell recruitment  in  CD26-deficient rats was associated with significantly reduced OVA-specific IgE-titres. See CD26 (dipeptidyl-peptidase IV)-dependent recruitment of T cells in a rat asthma model. Clin Exp Immunol. 2005 Jan;139(1):17-24

Yan and colleagues examined lymphocyte subpopulations, the response to pokeweed mitogen (PWM). Several changes were observed in the cytokine response to PWM. Furthermore, serum levels of total IgG, IgG1, IgG2a and IgE, were lower in sera of CD26(-/-) mice following PWM and they detected reduced IL-4, IL-2 and delayed IFN-gamma production in the CD26-/- mice after PWM challenge. The authors conclude that CD26 contributes to the regulation of development, maturation and migration of CD4(+) T, NK and NKT cells, cytokine secretion, T cell-dependent antibody production and immunoglobulin isotype switching of β cells, as outlined in  Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol. 2003 Jun;33(6) :1519-27.

The available evidence suggests that the enzymatic activity of DPP-4may not be essential for many of the T cell activating or co-stimulatory p ro p erties attributed to CD26, however not all ex p eriments have used both wildty p e and mutant CD26 molecules to examine this s p ecific question. Similar questions have been raised about CD26 in the brain. Moreover recent data examining the neurobiology of mutant Fischer 344 rats revealed unexpected changes in several parameters relating to CNS function including reduced body weight,  reduced water consumption, increased pain sensitivity in a non-habituated hot plate test, and a reduced stress-like responses in tasks like the open field (OF), social interaction (SI), and passive avoidance test were found. See Extreme reduction of dipeptidyl peptidase IV activity in F344 rat substrains is associated with various behavioral differences. Physiol Behav. 2003 Oct;80(1):123-34.

Analysis of the immune response in CD26-/- mice provides direct evidence for an essential role of CD26 in the control of Th1 immune responses, via TGF-b-1-dependent regulation of inflammation. CD26-/- mice exhibit diminished production of TGF-b-1 in response to antigenic stimulation, and markedly enhanced severity of experimental autoimmune encephalomyelitis (EAE). Furthermore, CD26-/- T cells exhibited enhanced proliferation and increased secretion of Th1-dependent cytokines such as IFN-g, IL-2, and TNF-a following antigenic stimulation. See TGF-beta1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26. J Immunol. 2007 Apr 1;178(7):4632-40