ABSTRACT
Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1ß isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1α/α) or the STAT1ß (Stat1ß/ß ) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1ß/ß mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1ß/ß mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1ß/ß mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.
Subject(s)
Killer Cells, Natural/cytology , Lymphopoiesis/physiology , STAT1 Transcription Factor/immunology , Animals , Bone Marrow Transplantation , Cell Line, Tumor , Cytotoxicity, Immunologic , Immunologic Surveillance/drug effects , Immunologic Surveillance/immunology , Interferon-Stimulated Gene Factor 3/deficiency , Interferon-Stimulated Gene Factor 3/genetics , Interferon-Stimulated Gene Factor 3/immunology , Interleukin-15/pharmacology , Interleukin-15 Receptor alpha Subunit , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Depletion , Lymphoid Tissue/cytology , Lymphoma/immunology , Lymphoma/pathology , Lymphopoiesis/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Specificity , Protein Isoforms/genetics , Protein Isoforms/immunology , Receptors, Interferon/deficiency , STAT1 Transcription Factor/deficiency , STAT1 Transcription Factor/genetics , Specific Pathogen-Free Organisms , Spleen/cytology , Interferon gamma ReceptorABSTRACT
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.
Subject(s)
Hematopoiesis, Extramedullary , Herpesviridae Infections/physiopathology , Muromegalovirus , Myeloid Cells/physiology , STAT1 Transcription Factor/physiology , Animals , Cells, Cultured , Female , Gene Deletion , Herpesviridae Infections/immunology , Herpesviridae Infections/metabolism , Killer Cells, Natural/immunology , Male , Mice, Inbred C57BL , Muromegalovirus/physiology , Receptor, Interferon alpha-beta/genetics , Receptors, Interferon/genetics , Receptors, Interleukin/genetics , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Spleen/pathology , Spleen/virology , Stress, Physiological , Virus ReplicationABSTRACT
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-ß (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.
