CD26 Surface Molecule Involvement in T Cell Activation and Lymphokine Synthesis in Rheumatoid and Other Inflammatory Synovitis

Gerli, Roberto; Muscat, Christopher; Bertotto, A; Bistoni, Onelia; Agea, Elisabetta; Tognellini, Rita; Fiorucci, G; Cesarotti, M; Bombardieri, Stefano

doi:10.1006/clin.1996.0091

Cited by 50 publications

(47 citation statements)

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“…In the clinical setting, patients with autoimmune diseases such Graves' disease and rheumatoid arthritis have increased levels of CD26 ϩ T cells in inflamed tissues such as thyroid and synovial membrane and fluids (14,37). In addition, enhancement of CD26 expression in these autoimmune diseases may correlate with disease severity (17,40). Moreover, it has been shown that T cells migrating through endothelial cell monolayers in vitro express high levels of CD26 (33,34), while the fact that chemokines play a key role in T-cell migration supports the notion that CD26/DPPIV may interact with these biological factors (23,44,47).…”

Section: Discussionmentioning

confidence: 90%

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

Ohnuma

Yamochi

Uchiyama

et al. 2005

Molecular and Cellular Biology

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CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptorassociated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-B. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigenspecific T-cell proliferation.CD26 is a widely distributed 110-kDa cell surface glycoprotein with known dipeptidyl peptidase IV (DPPIV) (EC 3.4.14.5) activity in its extracellular domain (16,38). This enzyme is capable of cleaving amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. While CD26 expression is enhanced following activation of resting T cells, CD4 ϩ CD26 high T cells respond maximally to recall antigens such as tetanus toxoid (TT) (39). Cross-linking of CD26 and CD3 with solid-phase immobilized monoclonal antibodies (MAbs) can induce T-cell costimulation and interleukin-2 (IL-2) production by either human CD4 ϩ T cells or Jurkat T-cell lines transfected with CD26 cDNA (16,56). In addition, anti-CD26 antibody treatment of T cells leads to a decrease in the surface expression of CD26 via its internalization, and such modulation results in an enhanced proliferative response to anti-CD3 or anti-CD2 stimulation as well as enhanced tyrosine phosphorylation of signaling molecules such as CD3 and p56-Lck (19). Moreover, we showed that DPPIV enzyme activity is required for CD26-mediated T-cell costimulation and various immune responses (23,45,58). We have recently shown that internalization of CD26 after cross-linking is mediated in part by the mannose-6-phosphate/insulin-like growth factor II receptor and that the interaction of CD26 and the mannose-6-phosphate/insulin-like growth factor II receptor plays a role in CD26-induced T-cell costimulation (20).In a recent study, we demonstrated that caveolin-1 is a binding protein of CD26 and that CD26 on activated memory T cells interacts with caveolin-1 on TT-loaded monocytes (43). In this interaction, the scaffolding domain (SCD) of caveolin-1, comprising residues 82 to 101...

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Section: Discussionmentioning

confidence: 90%

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

Ohnuma

Yamochi

Uchiyama

et al. 2005

Molecular and Cellular Biology

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“…Enhancement of CD26 expression in autoimmune diseases may correlate with disease severity (40,41), because patients with autoimmune diseases such as Grave's disease and rheumatoid arthritis have increased levels of CD26 ϩ T-cells in their peripheral blood as well as inflamed tissues, including thyroid and synovial fluids and membranes (9,42). These findings imply that CD26 ϩ T-cells play a role in the inflammation process and subsequent tissue destruction.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1

Ohnuma

Uchiyama

Yamochi

et al. 2007

Journal of Biological Chemistry

118

111

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CD26 is a widely distributed 110-kDa cell surface glycoprotein with an important role in T-cell costimulation. We demonstrated previously that CD26 binds to caveolin-1 in antigen-presenting cells, and following exogenous CD26 stimulation, Tollip and IRAK-1 disengage from caveolin-1 in antigen-presenting cells. IRAK-1 is then subsequently phosphorylated to up-regulate CD86 expression, resulting in subsequent T-cell proliferation. However, it is unclear whether caveolin-1 is a costimulatory ligand for CD26 in T-cells. Using soluble caveolin-1-Fc fusion protein, we now show that caveolin-1 is the costimulatory ligand for CD26, and that ligation of CD26 by caveolin-1 induces T-cell proliferation and NF-B activation in a T-cell receptor/ CD3-dependent manner. We also demonstrated that the cytoplasmic tail of CD26 interacts with CARMA1 in T-cells, resulting in signaling events that lead to NF-B activation. Ligation of CD26 by caveolin-1 recruits a complex consisting of CD26, CARMA1, Bcl10, and IB kinase to lipid rafts. Taken together, our findings provide novel insights into the regulation of T-cell costimulation via the CD26 molecule.

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“…Clinical observations also link CD26/DP IV to autoimmunity. Elevated numbers of CD26 ϩ CD4 ϩ T cells were described in peripheral blood and cerebrospinal and synovial fluids from patients with multiple sclerosis (27)(28)(29), and clinically active rheumatoid arthritis (30,31), respectively. Recently, the reversible, competitive DP IV inhibitors, Lys[Z(NO 2 )]-pyrrolidide (I40) and Lys[Z(NO 2 )]-thiazolidide (I49) have been extensively analyzed in vitro.…”

Section: O Ur Current Model For the Initiation Of T Cell-mediated Infmentioning

confidence: 99%

Targeting Dipeptidyl Peptidase IV (CD26) Suppresses Autoimmune Encephalomyelitis and Up-Regulates TGF-β1 Secretion In Vivo

Steinbrecher

Reinhold

Quigley

et al. 2001

The Journal of Immunology

139

115

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CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO2)]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-β1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-α production, I40 consistently up-regulated TGF-β1 secretion. A neutralizing anti-TGF-β1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-β1-mediated antiinflammatory effect at the site of pathology.

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CD26 Surface Molecule Involvement in T Cell Activation and Lymphokine Synthesis in Rheumatoid and Other Inflammatory Synovitis

Cited by 50 publications

References 0 publications

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

Caveolin-1 Triggers T-cell Activation via CD26 in Association with CARMA1

Targeting Dipeptidyl Peptidase IV (CD26) Suppresses Autoimmune Encephalomyelitis and Up-Regulates TGF-β1 Secretion In Vivo

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