In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

Abstract

Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

“…In addition, LTK shares a high degree of similarity with anaplastic lymphoma kinase, which is mutated in human cancers including adenocarcinomas of the lung, neuroblastomas, breast and esophageal cancers (37). TXK is a member of the Tec family of tyrosine kinases, which acts as Th1 cell-specific transcription factor (38). These results suggested that GSG2 may serve a crucial role in the establishment and progression of PCa.…”

Tyrosine kinase 2 is not limiting human antiviral type III interferon responses

“…However, murine data indicate that NK cell function is impaired in TYK2 deficiency . Thus, NK cell control of A‐MuLV‐induced lymphoma as well as RMA‐S and RMA‐Rae tumors was poor in TYK2 deficient mice, although the number of tumor infiltrating NK cells was comparable to wild‐type mice . The underlying mechanism is not completely resolved, but TYK2 deficiency was associated with reduced IFN‐γ production by NK cells .…”

“…Another important antiviral defense system that could limit virus susceptibility are NK cells. However, murine data indicate that NK cell function is impaired in TYK2 deficiency . Thus, NK cell control of A‐MuLV‐induced lymphoma as well as RMA‐S and RMA‐Rae tumors was poor in TYK2 deficient mice, although the number of tumor infiltrating NK cells was comparable to wild‐type mice .…”

Immunological Consequences of JAK Inhibition: Friend or Foe?

“…Lastly, modelling of Tyk2 suggests activation by a range of cytokines such as type I IFNs, IL-6, IL-10 and the IL-12 and IL-23 families (reviewed in [31]) . Tyk2 functionality has been shown in murine models to be crucial for T helper 1 (Th) 1-mediated immune responses and IL-12, signalling via Tyk2, plays a pivotal role in enhancing natural killer (NK) cell cytotoxicity [31][32][33]. As reviewed by Agnelo et al, Th1 cell differentiation also appears dependent upon a range of transcription factors, including TBET and STAT1/4, in addition to cytokines such as IL-12, IL-23 and IFN-Y; whereas, Th2 differentiation is dependent upon a number of transcription factors such as GATA-3, STAT6 and the cytokine IL-4 [34].…”