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

Center for Immunology and Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
The Journal of Immunology (Impact Factor: 4.92). 02/2005; 174(1):294-301. DOI: 10.4049/jimmunol.174.1.294
Source: PubMed


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.

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Available from: David Farrar
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    • "The insertion in mouse STAT2 alters the C-terminus and selectively disrupts its capacity to activate STAT4 [27]. However, this notion was negated by the finding that mice expressing a chimeric mouse STAT2 with human TAD domain were unable to activate STAT4 and trigger Th1 differentiation [28]. In fact, overexpression of mouse STAT2 in human U6 cell line that does not express STAT2 rescues IFNα response [21]. "
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    • "Therefore, although the precise role of T-bet in autoimmune inflammation remains elusive, these data show clearly that T-bet is not required for IL-17 production from CD4 T cells, reiterating the notion that Th17 effector cells develop independently of Th1 and Th2 cells. Consistent with this, STAT4-deficient mice are resistant to the chronic inflammatory disorders in which the IL-23–IL-17 pathway drives autoimmune disease, EAE, suggesting that STAT4 is required for development of pathogenic Th17 cells (Persky et al., 2005). Indeed, signaling through the IL-23R complex has been shown to phosphorylate STAT1, STAT3, and STAT4, as well as to induce the formation of STAT3/STAT4 heterodimers, suggesting that both STAT3 and STAT4 might be important for IL-17 production from CD4 T cells (Lin et al., 2005). "
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    • "Our previous studies demonstrated that although the human STAT2 C-terminus was required to promote IFN-α-dependent STAT4 activation in human fibroblasts (Farrar et al., 2000a), it was not sufficient to restore this pathway when expressed in murine T cells (Persky et al., 2005). This finding predicts that additional species-specific components of the IFNAR complex regulate STAT4 tyrosine phosphorylation. "
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