Abstract
CD4+ T cells regulate adaptive responses to pathogens by secreting unique subsets of cytokines that mediate inflammatory processes. The innate cytokines IL-12 and IFN-α/β regulate type I responses and promote acute IFN-γ secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-α/β-dependent STAT4 phosphorylation does not occur as efficiently in mice as it does in human T cells. In order to understand this species-specific pathway for IFN-α/β-dependent STAT4 activation, we have examined the molecular basis of STAT4 recruitment by the human IFNAR. In this report, we demonstrate that the N-domain of STAT4 interacts with the cytoplasmic domain of the human, but not the murine IFNAR2 subunit. This interaction mapped to a membrane-proximal segment of the hIFNAR2 spanning amino acids 299-333. Deletion of this region within the hIFNAR2 completely abolishes IFN-α/β-dependent STAT4 tyrosine phosphorylation when expressed in human IFNAR2-deficient fibroblasts. Thus, the human IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation.
Original language | English (US) |
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Pages (from-to) | 1864-1872 |
Number of pages | 9 |
Journal | Molecular Immunology |
Volume | 44 |
Issue number | 8 |
DOIs | |
State | Published - Mar 2007 |
Keywords
- Cytokine receptors
- Signal transduction
- T cells
ASJC Scopus subject areas
- Immunology
- Molecular Biology