Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo

J Immunol. 2006 Aug 1;177(3):1679-88. doi: 10.4049/jimmunol.177.3.1679.

Abstract

Dendritic cells (DCs) have been suggested to direct a type of Th differentiation through their cytokine profile, e.g., high IL-12/IL-23 for Th1 (named DC1/immunogenic DCs) and IL-10 for Th2 (DC2/tolerogenic DCs). Suppressor of cytokine signaling (SOCS)-3 is a potent inhibitor of Stat3 and Stat4 transduction pathways for IL-23 and IL-12, respectively. We thus hypothesize that an enhanced SOCS-3 expression in DCs may block the autocrine response of IL-12/IL-23 in these cells, causing them to become a DC2-type phenotype that will subsequently promote Th2 polarization of naive T cells. Indeed, in the present study we found that bone marrow-derived DCs transduced with SOCS-3 significantly inhibited IL-12-induced activation of Stat4 and IL-23-induced activation of Stat3. These SOCS-3-transduced DCs expressed a low level of MHC class II and CD86 on their surface, produced a high level of IL-10 but low levels of IL-12 and IFN-gamma, and expressed a low level of IL-23 p19 mRNA. Functionally, SOCS-3-transduced DCs drove naive myelin oligodendrocyte glycoprotein-specific T cells to a strong Th2 differentiation in vitro and in vivo. Injection of SOCS-3-transduced DCs significantly suppressed experimental autoimmune encephalomyelitis, a Th1 cell-mediated autoimmune disorder of the CNS and an animal model of multiple sclerosis. These results indicate that transduction of SOCS-3 in DCs is an effective approach to generating tolerogenic/DC2 cells that then skew immune response toward Th2, thus possessing therapeutic potential in Th1-dominant autoimmune disorders such as multiple sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Dendritic Cells / transplantation
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Female
  • Gene Expression Regulation / immunology
  • Immune Tolerance / genetics*
  • Immunophenotyping*
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / physiology
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins / antagonists & inhibitors
  • Interleukins / physiology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • STAT4 Transcription Factor / antagonists & inhibitors
  • STAT4 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / biosynthesis
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Suppressor of Cytokine Signaling Proteins / physiology
  • Th2 Cells / cytology
  • Th2 Cells / immunology*
  • Transduction, Genetic*

Substances

  • Il23a protein, mouse
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • STAT4 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Stat4 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Interleukin-12