Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases

J Immunol. 2008 May 1;180(9):6070-6. doi: 10.4049/jimmunol.180.9.6070.


Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3)(-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3)(-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3)(-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4(Stat3)(-/-) mouse because of the reduction in the expression of activated alpha4/beta1 integrins on CD4(Stat3)(-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3)(-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4(+) T cells results in an intrinsic developmental defect that renders CD4(Stat3)(-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Brain / immunology
  • Brain / pathology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Movement / genetics
  • Cell Movement / immunology*
  • Cytokines / immunology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / therapy
  • Eye / immunology
  • Eye / pathology
  • Forkhead Transcription Factors / immunology
  • Integrin alpha4beta1 / immunology
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / therapy
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Uveitis / genetics
  • Uveitis / immunology
  • Uveitis / pathology
  • Uveitis / therapy


  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Integrin alpha4beta1
  • STAT3 Transcription Factor
  • Stat3 protein, mouse