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IL-12, but not IFN-alpha, promotes STAT4 activation and Th1 development in murine CD4+ T cells expressing a chimeric murine/human Stat2 gene.

Humans and mice have evolved distinct pathways for Th1 cell development. Although IL-12 promotes CD4(+) Th1 development in both murine and human T cells, IFN-alphabeta drives Th1 development only in human cells. This IFN-alphabeta-dependent pathway is not conserved in the mouse species due in part to a specific mutation within murine Stat2. Restoration of this pathway in murine T cells would provide the opportunity to more closely model specific human disease states that rely on CD4(+) T cell responses to IFN-alphabeta. To this end, the C terminus of murine Stat2, harboring the mutation, was replaced with the corresponding human Stat2 sequence by a knockin targeting strategy within murine embryonic stem cells. Chimeric m/h Stat2 knockin mice were healthy, bred normally, and exhibited a normal lymphoid compartment. Furthermore, the murine/human STAT2 protein was expressed in murine CD4(+) T cells and was activated by murine IFN-alpha signaling. However, the murine/human STAT2 protein was insufficient to restore full IFN-alpha-driven Th1 development as defined by IFN-gamma expression. Furthermore, IL-12, but not IFN-alpha, promoted acute IFN-gamma secretion in collaboration with IL-18 stimulation in both CD4(+) and CD8(+) T cells. The inability of T cells to commit to Th1 development correlated with the lack of STAT4 phosphorylation in response to IFN-alpha. This finding suggests that, although the C terminus of human STAT2 is required for STAT4 recruitment and activation by the human type I IFNAR (IFN-alphabetaR), it is not sufficient to restore this process through the murine IFNAR complex.

Pubmed ID: 15611252

Authors

  • Persky ME
  • Murphy KM
  • Farrar JD

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

January 1, 2005

Associated Grants

None

Mesh Terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Chimera
  • DNA-Binding Proteins
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoprecipitation
  • Interferon-alpha
  • Interleukin-12
  • Lymphocyte Activation
  • Membrane Proteins
  • Mice
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon
  • STAT2 Transcription Factor
  • STAT4 Transcription Factor
  • Th1 Cells
  • Trans-Activators