Partial Impairment of Cytokine Responses in Tyk2-Deficient Mice

Abstract

To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2-/- mice display reduced responses to IFNalpha/beta and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNgamma signaling is also impaired in Tyk2-/- mice. Tyk2-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction. Tyk2-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge. These data imply a selective contribution of Tyk2 to the signals triggered by various biological stimuli and cytokine receptors.

Control of Leishmania major in the absence of Tyk2 kinase

“…The response to other cytokines that in the past were thought to signal via Tyk2 kinase (e.g. IL-3, IL-6, IL-10 and G-CSF) was unaltered in Tyk2 -/-cells [17,18]. The LPSinduced expression of iNOS in macrophages was completely dependent on Tyk2 [17].…”

“…In vitro, costimulation of macrophages with IFN- § / g plus L. major led to a strong induction of iNOS [24]. LPS plus IFN- § / g or LPS alone (which requires endogenously produced IFN- § / g for the induction of iNOS [25,26]) activated wild-type, but not Tyk2 -/-peritoneal exudate macrophages for the production of NO [17] (Fig. 8A).…”

“…IL-3, IL-6, IL-10 and G-CSF) was unaltered in Tyk2 -/-cells [17,18]. The LPSinduced expression of iNOS in macrophages was completely dependent on Tyk2 [17]. Only very few data are available on the role of Tyk2 in the immune response in vivo.…”

“…Activation of Tyk2 and Jak2 kinase by IL-12 is thought to be a prerequisite for the subsequent tyrosine-phosphorylation of STAT3 and STAT4 [16]. Recent in vitro analyses with spleen cells from naive wild-type versus Tyk2 -/-mice revealed that the activation of STAT4 by IL-12 is reduced, but still detectable in the absence of Tyk2 kinase [17,18]. Similarly, in macrophages, myeloid precursor cells and embryonic fibroblasts from Tyk2 -/-cells the signaling response to type I interferons (IFN- § / g ), which previously were also shown to activate Tyk2 kinase, was only partially impaired compared to control cells.…”

“…Only very few data are available on the role of Tyk2 in the immune response in vivo. Tyk2 deficiency caused a reduced cytotoxic T cell response in mice infected with the lymphocytic choriomeningitis virus, led to an elevated viral replication in the spleens of mice infected with vaccinia virus [17], and protected the mice against fatal endotoxin shock [19].…”