TYK2 is a key regulator of the surveillance of B lymphoid tumors

Abstract

Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelsoninduced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2 -/-cells were unaltered, but the high susceptibility of TYK2 -/-mice resulted from an impaired tumor surveillance, and accordingly, TYK2 -/-A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2 -/-NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2 -/-TYK2 +/-mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance. IntroductionThe JAK-STAT pathway regulates cell proliferation, differentiation, and survival in hematopoietic cells (1, 2). Binding of a cytokine to its cognate receptor activates receptor-associated JAKs which in turn mediate the subsequent tyrosine phosphorylation of STAT proteins. Phosphorylated STAT proteins form dimers, translocate to the nucleus, and bind to specific DNA elements to induce or modulate expression of target genes. Gene knockout studies in mice underlined the vital role of the JAK-STAT pathway for hematopoiesis and other developmental processes (3).Recent interest had focused on the role of the JAK-STAT pathway in tumor formation. Aberrant activation of JAK-STAT signaling had been shown in multiple solid tumors and leukemia (4-9). In particular, STAT3 and STAT5 have drawn much attention; both transcription factors display oncogenic properties when expressed ectopically. A constitutively active mutant of STAT3 was shown to transform rat fibroblasts (10), and the enforced expression of WT STAT5 in the lymphoid lineage induced T cell leukemia in mice (11). In addition, JAK1 has been implicated in transformation by the v-abl as well as by the v-src oncogene (12, 13), and constitutive activation of JAK2 as in the TEL-JAK2 oncogene suffices to induce leukemia in mice and humans (14, 15). On the other hand, JAK1 was shown to be a tumor suppressor downstream of IFN-γ in a B lymphoid tumor model (16). A role as tumor suppressor downstream of IFN-γ has also been attributed to STAT1 (17-21). STAT1 -/-mice have been repeatedly used to study the role of IFN-γ in tumorigenesis and tumor surveillance (18,19). Recent evidence also proposed that STAT1 acted as a tumor suppressor by modulating apoptosis (22).TYK2 has been initially defined as a mediator of IFN-α/β sign...

Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity

“…Both, IL-12 and IL-18 triggered cytotoxicity was reduced in Tyk2 -/-NK cells when tested against the NK target cell line YAC-1. In line with this, ex vivo derived and IL-2 expanded Tyk2 -/-NK cells killed YAC-1 cells as well as lymphoma cells less efficiently (111).…”

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

“…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 . Reduced responses to IL‐12 and type‐I IFN might account for inappropriate NK cell activation in vivo .…”

“…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 .…”

“…Additional defects were described in tumor models. TYK2 deficient NK cells or cytotoxic T lymphocytes, poorly responsive to IL‐12, were unable to control B lymphoid tumors or thymoma in mice.…”

STATs in NK-Cells: The Good, the Bad, and the Ugly

“…Consequently, Tyk2 −/− NK-cells possess a severely impaired cytolytic activity, do not efficiently clear certain infections, and display an impaired tumor immune surveillance (55–58). In line, patients with autosomal recessive Tyk2 mutations suffer from recurrent bacterial and viral infections and display impaired NK-cell responses (59).…”