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

Steinbrecher, Andreas; Reinhold, Dirk; Quigley, Laura; Gado, Ameer M; Tresser, Nancy; Izikson, Leonid; Born, Ilona; Faust, Jürgen; Neubert, Klaus; Martin, Roland; Ansorge, Siegfried; Brocke, Stefan

doi:10.4049/jimmunol.166.3.2041

Cited by 139 publications

(123 citation statements)

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“…In indicated experiments, mice were immunized for a second time with 200 mg MOG peptide in CFA (Sigma-Aldrich) containing 800 mg killed M. tuberculosis (Sigma-Aldrich) 7 d after primary immunization. Mice were monitored daily for clinical signs of EAE and graded on a scale of increasing severity from 0 to 5, according to a previously published grading scale (26) and detailed in Supplemental Table I. Daily clinical scores were calculated as the average of all individual disease scores within each group.…”

Section: Induction and Clinical Evaluation Of Eaementioning

confidence: 99%

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Haroon

Drögemüller

Händel

et al. 2011

The Journal of Immunology

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108

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Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein35–55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/fl mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130fl/fl mice, whereas gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/fl mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130fl/fl mice resulted in a reduction of CNS regulatory Foxp3+ CD4 T cells and an increase of IL-17–, IFN-γ–, and TNF-producing CD4 as well as IFN-γ– and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130– Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130–STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130–Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130–STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.

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Section: Induction and Clinical Evaluation Of Eaementioning

confidence: 99%

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Haroon

Drögemüller

Händel

et al. 2011

The Journal of Immunology

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108

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“…The CD26 molecule functions as the cell membrane-associated exopeptidase dipeptidyl peptidase (DP) 4 IV (EC 3.4.14.5), an enzyme capable of cleaving N-terminal dipeptides from polypeptides with either proline or alanine residues at the penultimate position (1)(2)(3). Many recent reports have demonstrated that CD26/DP IV serves as an important regulator of immune responses by affecting T cell activation, proliferation, and cytokine production (1)(2)(3)(4)(5)(6)(7)(8). Subsequently, multiple roles were predicted for CD26/DP IV in leukocyte homing and inflammation.…”

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confidence: 99%

“…Notably, many ligands engaging membrane CD26/DP IV at the T cell surface can efficiently induce the regulatory cytokine TGF-␤1 in T cells and inhibit T cell activation and DNA synthesis (8,19,23). Thus, we and others have shown that inhibition of CD26/DP IV activity on human or mouse T cells by synthetic or naturally occurring inhibitory ligands results in TGF-␤1-mediated suppression of IL-2 and IFN-␥ production, as well as in suppression of T cell proliferation in vitro (4,8,19,23).…”

mentioning

confidence: 99%

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

Preller

Gerber

Wrenger

et al. 2007

The Journal of Immunology

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The T cell marker CD26/dipeptidyl peptidase (DP) IV is associated with an effector phenotype and markedly elevated in the human CNS disorder multiple sclerosis. However, little is known about the in vivo role of CD26/DP IV in health and disease, and the underlying mechanism of its function in CNS inflammation. To directly address the role of CD26/DP IV in vivo, we examined Th1 immune responses and susceptibility to experimental autoimmune encephalomyelitis in CD26−/− mice. We show that gene deletion of CD26 in mice leads to deregulation of Th1 immune responses. Although production of IFN-γ and TNF-α by pathogenic T cells in response to myelin Ag was enhanced in CD26−/− mice, production of the immunosuppressive cytokine TGF-β1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-β1 production, responsiveness to external TGF-β1 was normal in T cells from CD26−/− mice, excluding alterations in TGF-β1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-β1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-β1 production in T cells from CD26−/− mice. The striking functional deregulation of Th1 immunity was also seen in vivo. Thus, clinical experimental autoimmune encephalomyelitis scores were significantly increased in CD26−/− mice immunized with peptide from myelin oligodendrocyte glycoprotein. These results identify CD26/DP IV as a nonredundant inhibitory receptor controlling T cell activation and Th1-mediated autoimmunity, and may have important therapeutic implications for the treatment of autoimmune CNS disease.

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“…CD26 is also involved in T-cell activation, owing to its association with CD45, mannose 6-phosphate/insulin-like growth factor II receptor and adenosine deaminase (ADA) (Morimoto et al, 1989;Dang et al, 1990aDang et al, -d, 1991Torimoto et al, 1991;Kameoka et al, 1993;Morrison et al, 1993;Ikushima et al, 2000). Additionally, its DPPIV enzyme activity has a key role in various aspects of T-cell activation, as demonstrated by studies using DPPIV inhibitors, soluble CD26/DPPIV molecules or CD26 genetic mutants (Flentke et al, 1991;Tanaka et al, 1993Tanaka et al, , 1994Steinbrecher et al, 2001). Besides its involvement in normal T-cell function, CD26 may also have a role in the development of certain tumors (Tanaka et al, 1995;Stecca et al, 1997;Bauvois et al, 1999;Dang and Morimoto, 2002).…”

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confidence: 99%

Effect of CD26/dipeptidyl peptidase IV on Jurkat sensitivity to G2/M arrest induced by topoisomerase II inhibitors

et al. 2003

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CD26/dipeptidyl peptidase IV (DPPIV) is a surface antigen with multiple functions, including a role in T-cell activation and the development of certain human cancers. We previously demonstrated that CD26/DPPIV enhanced sensitivity of Jurkat cells to doxorubicin. We now show that expression of CD26/DPPIV enhanced sensitivity of CD26 Jurkat transfectants to G 2 -M arrest mediated by the antineoplastic agent etoposide. The increased sensitivity to etoposide-induced G 2 -M arrest was associated with disruption of cell cycle-related events, including hyperphosphorylation of p34 cdc2 kinase, change in cdc25C expression and phosphorylation, and alteration in cyclin B1 expression. CD26/DPPIV-associated enhancement of doxorubicin and etoposideinduced G 2 -M arrest was also observed in serum-free media, suggesting an effect of CD26 on cell-derived processes rather than serum-derived factors. Importantly, our work elucidated a potential mechanism for the enhanced susceptibility of CD26-expressing Jurkat cells to the topoisomerase II inhibitors by demonstrating that CD26/DPPIV surface expression was associated with increased topoisomerase II a levels and enhanced enzyme activity. Besides being the first to show a functional association between the multifaceted molecule CD26 and the key cellular protein topoisomerase II a, our studies provide additional evidence of a potential role for CD26 in the treatment of selected malignancies.

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

Cited by 139 publications

References 58 publications

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

TGF-β1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26

Effect of CD26/dipeptidyl peptidase IV on Jurkat sensitivity to G2/M arrest induced by topoisomerase II inhibitors

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