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

Abstract

Tyrosine kinase 2 (Tyk2) contributes to the signals triggered by IL-12 for IFN-c production by NK cells and T cells. We found in this study that Tyk2-deficient (-/-) mice showed increased susceptibility at the early stage after an i.p. infection with Listeria monocytogenes, accompanied by impaired IFN-c production. The numbers of both MHC class Ib (H2-M3)-or MHC class Ia (K b )-restricted CD8 + T cells producing IFN-c and exhibiting cytotoxicity were significantly decreased in Tyk2 -/-mice after infection with L. monocytogenes. Using an adoptive transfer system of OT-I cells expressing OVA 257-264 /K b -specific TCR into Tyk2 -/-mice followed by challenge with recombinant L. monocytogenes expressing OVA, we found that the defective Tyk2 signaling in the host environment was at least partially responsible for the impaired CD8 + T cytotoxic-1 (Tc1) cell responses in Tyk2 -/-mice following the infection. Adoptive transfer with MHC class Ib-or MHC class Ia-binding peptide-pulsed BM-derived DC from Tyk2 -/-mice induced lower levels of the Ag-specific CD8 + Tc1 cells producing IFN-c. These results suggest that Tyk2 signaling is also important for DC function in the induction of MHC class Ia-and class Ib-restricted CD8 + Tc1 cells following L. monocytogenes infection.

Tyk2-Dependent Bystander Activation of Conventional and Nonconventional Th1 Cell Subsets Contributes to Innate Host Defense against Listeria monocytogenes Infection

“…4B), indicating that the impaired IFN-g production of KO CD4 T cells was not due to a decreased bacterial burden. The difference in bacterial number between WT and Tyk2 KO mice was smaller compared with our previous study (27), possibly because of the altered bacterial virulence and different number of inoculated bacteria. By examining IFN-g production of various cell subsets at day 2 postinfection, it was revealed that the majority of IFN-g-producing cells were NK cells, which were reduced in Tyk2 KO mice (Fig.…”

“…Tyk2-deficient mice showed an impaired early protection against L. monocytogenes infection (27). Although Tyk2-dependent IFN-g production by NK cells, NK-T cells, MP CD8 T cells, as well as TCR gd T cells might be involved in the early protection against listerial infection, earlier results also suggest a role of Th1 cells.…”

Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance

“…have failed to show any defects in Tyk2 À/À DC maturation and their ability to stimulate T-cell proliferation in vitro (15). Nevertheless, we cannot yet fully exclude a contribution of Tyk2 for DC functions in vivo.…”

“…Mice deficient for Tyk2 (Tyk2 À/À mice) are viable and fertile but were described to have defects in type I IFN, IL12, and also type II IFN (IFNg) signaling (11,12). Tyk2 À/À mice show an increased susceptibility to various pathogens (11,(13)(14)(15) but are resistant against lipopolysaccharide (LPS)-induced endotoxin shock (16). In addition, Tyk2 is a key regulator for Th1/Th2 balance (17).…”

Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

“…41 Moreover, it has recently been shown that Tyk2 Ϫ/Ϫ mice exhibit increased susceptibility to an infection with Listeria monocytogenes. 42 In humans, a hyper-IgE syndrome patient who lacks Tyk2 also shows unusual susceptibility to various microorganisms including viruses, fungi, and mycobacteria. 37 These results indicate that Tyk2 plays a nonredundant role in the protective immune responses against pathogens in both mice and humans.…”