Pathways that Regulate Antigrowth Effects of Interferons

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Type 1 interferons are critical regulators of innate immunity and antiviral responses. To exert their actions they often also inhibit cell growth. The mechanisms by which interferons inhibit cell proliferation vary and in many circumstances are not well understood. In some cells type 1 interferons (IFN_/13) induce apoptosis; in other cell lines IFNod_ inhibit cell growth without induction of apoptosis, and in certain circumstances these cytokines actually prevent apoptosis by other stimuli. In vivo and in cell culture, IFN_t3 stimulates apoptosis of immature B cells. Preliminary results using bll-7-dependent B cells from knock out mice that do not express Statl, Statl, Stat5a/b, or Tyk2 indicate that interferon activation of early response genes regulated by the Statl and Stat2 transcription factors is not necessary for the apoptotic actions of IFNcdl3. However, expression of the tyrosine kinase Tyk2 is required for IFNodl3 stimulated death of pro B cells as well as activation of Stat3 by these cytokines. These in vitro results are also seen in vivo where Tyk2-null mice are resistant to LCMV stimulated loss of B cells from bone marrow and spleen. We hypothesize that IFN_ mediated apoptosis requires the kinase activity of Tyk2, resulting in tyrosine phosphorylation of Stat3 and regulation of genes by this transcription factor that lead to programmed cell death of pro B cells. The Specific Aims are: 1. Determine the domains in Tyk2 required for IFN_ stimulated apoptosis of IL-7-dependent bone marrow-derived B cells. 2. Determine the role of phosphorylated Stat3 in IFNI_ stimulated PCD of B cells 3. Identify proteins in primary IL-7 dependent B cells that require the expression of Tyk2 to activate Stat3 and cause IFNI_ stimulated apoptosis.