IL-12, but Not IFN- alpha , Promotes STAT4 Activation and Th1 Development in Murine CD4 super(+) T Cells Expressing a Chimeric Murine/Human Stat2 Gene

• Published in: The Journal of immunology (1950) 2005-01, Vol.174 (1), p.294-301
• Main Authors: Persky, Meredith E, Murphy, Kenneth M, Farrar, JDavid
• Format: Article
• Language: English
• ISSN: 0022-1767

Humans and mice have evolved distinct pathways for Th1 cell development. Although IL-12 promotes CD4 super(+) Th1 development in both murine and human T cells, IFN- alpha beta drives Th1 development only in human cells. This IFN- alpha beta - 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 super(+) T cell responses to IFN- alpha beta . 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 super(+) 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 super(+) and CD8 super(+) 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- alpha beta R), it is not sufficient to restore this process through the murine IFNAR complex.