Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.

The members of the signal transducer and activator of transcription (STAT) family of transcription factors modulate the development and function of natural killer (NK) cells. NK cell-mediated tumor surveillance is particularly important in the body's defense against hematological malignancies such as leukemia. STAT3 inhibitors are currently being developed, although their potential effects on NK cells are not clear. We have investigated the function of STAT3 in NK cells with Stat3(Δ/Δ)Ncr1-iCreTg mice, whose NK cells lack STAT3. In the absence of STAT3, NK cells develop normally and in normal numbers, but display alterations in the kinetics of interferon-γ (IFN-γ) production. We report that STAT3 directly binds the IFN-γ promoter. In various in vivo models of hematological diseases, loss of STAT3 in NK cells enhances tumor surveillance. The reduced tumor burden is paralleled by increased expression of the activating receptor DNAM-1 and the lytic enzymes perforin and granzyme B. Our findings imply that STAT3 inhibitors will stimulate the cytolytic activity of NK cells against leukemia, thereby providing an additional therapeutic benefit.

TLR 2 and CD14 mediate innate immunity and lung inflammation to staphylococcal Panton-Valentine leukocidin in vivo.

The pore-forming toxin Panton-Valentine leukocidin (PVL) is carried by community-acquired methicillin-resistant Staphylococcus aureus and associated with necrotizing pneumonia together with poor prognosis of infected patients. Although the cell-death-inducing properties of PVL have previously been examined, the pulmonary immune response to PVL is largely unknown. Using an unbiased transcriptional profiling approach, we show that PVL induces only 29 genes in mouse alveolar macrophages, which are associated with TLR signaling. Further studies indicate that PVL directly binds to TLR2 and induces immune responses via NF-κB in a TLR2, CD14, MyD88, IL-1R-associated kinase 1, and TNFR-associated factor 6-dependent manner. PVL-mediated inflammation is independent of pore formation but strongly depends on the LukS subunit and is suppressed in CD14/TLR2(-/-) cells. In vivo PVL or LukS induced a robust inflammatory response in lungs, which was diminished in CD14/TLR2(-/-) mice. These results highlight the proinflammatory properties of PVL and identify CD14/TLR2 as an essential receptor complex for PVL-induced lung inflammation.

Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1.

Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.