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

Meredith E. Persky, Kenneth M. Murphy, J. David Farrar

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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-αβ drives Th1 development only in human cells. This IFN-αβ-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-αβ. 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-α signaling. However, the murine/human STAT2 protein was insufficient to restore full IFN-α-driven Th1 development as defined by IFN-γ expression. Furthermore, IL-12, but not IFN-α, promoted acute IFN-γ 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-α. This Unding suggests that, although the C terminus of human STAT2 is required for STAT4 recruitment and activation by the human type I IFNAR (IFN-αβR), it is not sufficient to restore this process through the murine IFNAR complex.

Original languageEnglish (US)
Pages (from-to)294-301
Number of pages8
JournalJournal of Immunology
Volume174
Issue number1
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'IL-12, but not IFN-α, promotes STAT4 activation and Th1 development in murine CD4+ T cells expressing a chimeric murine/human Stat2 gene'. Together they form a unique fingerprint.

Cite this