Transglutaminase 2 exacerbates experimental autoimmune encephalomyelitis through positive regulation of encephalitogenic T cell differentiation and inflammation

Clin Immunol. 2012 Nov;145(2):122-32. doi: 10.1016/j.clim.2012.08.009. Epub 2012 Aug 23.


The increased activity of transglutaminase 2 (TG2) in various inflammatory and fibrotic conditions results in the development of numerous disease processes. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is an inflammatory and demyelinating disease of the central nervous system and is mediated by many inflammatory cytokines and mediators. We examined the role of TG2 in encephalitogenic CD4(+) T cell responses and EAE development using mice lacking TG2 (TG2(-/-)). TG2(-/-) mice showed decreased disease severity as compared with wild-type (WT) mice. Treatment with cysteamine, a TG2 inhibitor, ameliorated disease severity in WT mice. Exacerbated disability in WT mice resulted from the increased infiltration of cytokine-producing CD4(+) T cells and sustained expression of inflammatory cytokines and mediators in the lesion. The increased number of IL-17- and IFN-γ-producing cells in the spinal cord resulted from peripheral expansion of these cells after immunization with myelin-derived antigen. In vitro differentiation of WT and TG2(-/-) splenocytes revealed that proliferation and activation-induced cell death did not differ, but differentiation into IL-17- or IFN-γ-producing cells was increased in WT mice. Adoptive transfer experiments revealed that pathogenic CD4(+) T cell differentiation and disease progression were caused by both the T cell-intrinsic and -extrinsic effects of TG2. This study is the first to report a pathogenic role for TG2 in the EAE progress and suggests that therapeutic targeting of TG2 may be effective against multiple sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens / immunology
  • Antigens / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cell Proliferation / drug effects
  • Cysteamine / pharmacology
  • Cysteamine / therapeutic use
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • GTP-Binding Proteins / antagonists & inhibitors*
  • GTP-Binding Proteins / deficiency
  • GTP-Binding Proteins / genetics
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Mice
  • Mice, Knockout
  • Myelin Sheath / immunology
  • Protein Glutamine gamma Glutamyltransferase 2
  • Severity of Illness Index
  • Signal Transduction
  • Spinal Cord / drug effects
  • Spinal Cord / enzymology
  • Spinal Cord / immunology
  • Transglutaminases / antagonists & inhibitors*
  • Transglutaminases / deficiency
  • Transglutaminases / genetics


  • Antigens
  • Interleukin-17
  • Cysteamine
  • Interferon-gamma
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins