Tyk2 Plays a Restricted Role in IFNα Signaling, Although It Is Required for IL-12-Mediated T Cell Function

Abstract

Janus kinases (Jaks) play an important role in signal transduction via cytokine receptors. Tyk2 is a Janus kinase, and we developed tyk2-deficient mice to study the requirement for tyk2 in vivo. Tyk2-deficient mice show no overt developmental abnormalities; however, they display a lack of responsiveness to a small amount of IFNalpha, although a high concentration of IFNalpha can fully transduce its signal even in the absence of tyk2. Furthermore, IL-12-induced T cell function is defective in these mice. In contrast, these mice respond normally to IL-6 and IL-10, both of which activate tyk2 in vitro. These observations demonstrate that tyk2 plays only a restricted role in mediating IFNalpha-dependent signaling while being required in mediating IL-12-dependent biological responses.

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 an earlier study Shimoda et al [18] concluded that Tyk2 is indispensable for the IL-12 response of unseparated CD3 + spleen cells as well as for the development of CD4 + Th1 cells. Here, we found that Tyk2 dependency was most striking in CD8 + T cells, in which the production of IFN-+ in response to IL-12/IL-18 was strongly suppressed throughout infection.…”

“…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.…”

An important role of Tyk2 in APC function of dendritic cells for priming CD8+ T cells producing IFN‐γ

“…Furthermore, these mice normally respond to IL-6 and IL-10, suggesting that Tyk2 is dispensable for mediating IL-6 and IL-10 signaling and does not play major roles in IFN-a signaling. We and others have recently shown that the IL-12-induced functions of NK cells and CD4 + T cells are defective in Tyk2 -/-mice [14][15][16][17]. Tyk2 -/-mice showed reduced CD8 + CTL responses following infection with lymphocytic choriomeningitis virus [15].…”

“…Tyk2-deficient (-/-) mice display a lack of responsiveness to small amounts of IFN-a, but they respond normally to high concentrations of IFN-a [14,15]. Furthermore, these mice normally respond to IL-6 and IL-10, suggesting that Tyk2 is dispensable for mediating IL-6 and IL-10 signaling and does not play major roles in IFN-a signaling.…”