title: TGF-beta1-mediated control of central nervous system inflammation and autoimmunity through the inhibitory receptor CD26.
abstract: 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-gamma and TNF-alpha by pathogenic T cells in response to myelin Ag was enhanced in CD26(-/-) mice, production of the immunosuppressive cytokine TGF-beta1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-beta1 production, responsiveness to external TGF-beta1 was normal in T cells from CD26(-/-) mice, excluding alterations in TGF-beta1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-beta1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-beta1 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.
authors: Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors: Vera
authors: V
authors: Preller
authors: Annegret
authors: A
authors: Gerber
authors: Sabine
authors: S
authors: Wrenger
authors: Mauro
authors: M
authors: Togni
authors: Didier
authors: D
authors: Marguet
authors: Janine
authors: J
authors: Tadje
authors: Uwe
authors: U
authors: Lendeckel
authors: Christoph
authors: C
authors: Röcken
authors: Jürgen
authors: J
authors: Faust
authors: Klaus
authors: K
authors: Neubert
authors: Burkhart
authors: B
authors: Schraven
authors: Roland
authors: R
authors: Martin
authors: Siegfried
authors: S
authors: Ansorge
authors: Stefan
authors: S
authors: Brocke
authors: Dirk
authors: D
authors: Reinhold
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002490:Central Nervous System / Q000201:enzymology / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017384:Sequence Deletion; D018417:Th1 Cells / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1; D018819:Dipeptidyl Peptidase 4