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1.
Blood ; 143(11): 1049-1054, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38052031

ABSTRACT

ABSTRACT: We show that red cell exchange (RCE) treats hyperleukocytosis in acute leukemia. RCE provided similar leukoreduction to standard therapeutic leukoreduction and could be superior in patients with severe anemia or monocytic leukemias or when requiring rapid treatment.


Subject(s)
Leukemia, Monocytic, Acute , Leukemia, Myeloid, Acute , Leukostasis , Adult , Humans , Leukostasis/therapy , Leukemia, Myeloid, Acute/therapy , Leukemia, Monocytic, Acute/therapy , Acute Disease , Leukapheresis , Leukocytosis/therapy
3.
J Exp Med ; 217(5)2020 05 04.
Article in English | MEDLINE | ID: mdl-32150623

ABSTRACT

In chronic infections, the immune response fails to control virus, leading to persistent antigen stimulation and the progressive development of T cell exhaustion. T cell effector differentiation is poorly understood in the context of exhaustion, but targeting effector programs may provide new strategies for reinvigorating T cell function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator of antiviral T cell immunity, where loss of Trib1 led to a sustained enrichment of effector-like KLRG1+ T cells, enhanced function, and improved viral control. Single-cell profiling revealed that Trib1 restrains a population of KLRG1+ effector CD8 T cells that is transcriptionally distinct from exhausted cells. Mechanistically, we identified an interaction between Trib1 and the T cell receptor (TCR) signaling activator, MALT1, which disrupted MALT1 signaling complexes. These data identify Trib1 as a negative regulator of TCR signaling and downstream function, and reveal a link between Trib1 and effector versus exhausted T cell differentiation that can be targeted to improve antiviral immunity.


Subject(s)
Cell Differentiation , Intracellular Signaling Peptides and Proteins/metabolism , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Amino Acid Sequence , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line , Chronic Disease , Humans , Immunity , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/deficiency , Lymphocyte Activation/immunology , Lymphocyte Subsets/immunology , Lymphocytic choriomeningitis virus/immunology , Mice, Inbred C57BL , Mice, Knockout , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/metabolism , Phenotype , Protein Binding , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Transcription, Genetic , Viral Load
4.
Curr Opin Hematol ; 27(1): 27-33, 2020 01.
Article in English | MEDLINE | ID: mdl-31688456

ABSTRACT

PURPOSE OF REVIEW: Lineage commitment is governed by instructive and stochastic signals, which drive both active induction of the lineage program and repression of alternative fates. Eosinophil lineage commitment is driven by the ordered interaction of transcription factors, supported by cytokine signals. This review summarizes key findings in the study of eosinophil lineage commitment and examines new data investigating the factors that regulate this process. RECENT FINDINGS: Recent and past studies highlight how intrinsic and extrinsic signals modulate transcription factor network and lineage decisions. Early action of the transcription factors C/EBPα and GATA binding protein-1 along with C/EBPε supports lineage commitment and eosinophil differentiation. This process is regulated and enforced by the pseudokinase Trib1, a regulator of C/EBPα levels. The cytokines interleukin (IL)-5 and IL-33 also support early eosinophil development. However, current studies suggest that these cytokines are not specifically required for lineage commitment. SUMMARY: Together, recent evidence suggests a model where early transcription factor activity drives expression of key eosinophil genes and cytokine receptors to prime lineage commitment. Understanding the factors and signals that control eosinophil lineage commitment may guide therapeutic development for eosinophil-mediated diseases and provide examples for fate choices in other lineages.


Subject(s)
CCAAT-Enhancer-Binding Proteins/metabolism , Eosinophils/metabolism , GATA1 Transcription Factor/metabolism , Interleukin-33/biosynthesis , Interleukin-5/biosynthesis , Signal Transduction , Humans , Intracellular Signaling Peptides and Proteins , Protein Serine-Threonine Kinases/antagonists & inhibitors
5.
Blood ; 133(22): 2413-2426, 2019 05 30.
Article in English | MEDLINE | ID: mdl-30917956

ABSTRACT

Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.


Subject(s)
Eosinophils/metabolism , Gene Expression Regulation , Granulocyte-Macrophage Progenitor Cells/metabolism , Intracellular Signaling Peptides and Proteins/biosynthesis , Myelopoiesis , Neutrophils/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Eosinophils/cytology , Granulocyte-Macrophage Progenitor Cells/cytology , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Transgenic , Neutrophils/cytology , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/genetics
6.
PLoS One ; 11(5): e0155408, 2016.
Article in English | MEDLINE | ID: mdl-27191957

ABSTRACT

Trib2 is highly expressed in human T cell acute lymphoblastic leukemia (T-ALL) and is a direct transcriptional target of the oncogenic drivers Notch and TAL1. In human TAL1-driven T-ALL cell lines, Trib2 is proposed to function as an important survival factor, but there is limited information about the role of Trib2 in primary T-ALL. In this study, we investigated the role of Trib2 in the initiation and maintenance of Notch-dependent T-ALL. Trib2 had no effect on the growth and survival of murine T-ALL cell lines in vitro when expression was blocked by shRNAs. To test the function of Trib2 on leukemogenesis in vivo, we generated Trib2 knockout mice. Mice were born at the expected Mendelian frequencies without gross developmental anomalies. Adult mice did not develop pathology or shortened survival, and hematopoiesis, including T cell development, was unperturbed. Using a retroviral model of Notch-induced T-ALL, deletion of Trib2 unexpectedly decreased the latency and increased the penetrance of T-ALL development in vivo. Immunoblotting of primary murine T-ALL cells showed that the absence of Trib2 increased C/EBPα expression, a known regulator of cell proliferation, and did not alter AKT or ERK phosphorylation. Although Trib2 was suggested to be highly expressed in T-ALL, transcriptomic analysis of two independent T-ALL cohorts showed that low Trib2 expression correlated with the TLX1-expressing cortical mature T-ALL subtype, whereas high Trib2 expression correlated with the LYL1-expressing early immature T-ALL subtype. These data indicate that Trib2 has a complex role in the pathogenesis of Notch-driven T-ALL, which may vary between different T-ALL subtypes.


Subject(s)
Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Notch/metabolism , Animals , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Line, Tumor , Disease Models, Animal , Gene Expression , Gene Targeting , Genetic Loci , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Knockout , Penetrance , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction
7.
Biochem Soc Trans ; 43(5): 1112-5, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26517933

ABSTRACT

The tribbles protein family, an evolutionarily conserved group of pseudokinases, have been shown to regulate multiple cellular events including those involved in normal and malignant haematopoiesis. The three mammalian Tribbles homologues, Trib1, Trib2 and Trib3 are characterized by conserved motifs, including a pseudokinase domain and a C-terminal E3 ligase-binding domain. In this review, we focus on the role of Trib (mammalian Tribbles homologues) proteins in mammalian haematopoiesis and leukaemia. The Trib proteins show divergent expression in haematopoietic cells, probably indicating cell-specific functions. The roles of the Trib proteins in oncogenesis are also varied and appear to be tissue-specific. Finally, we discuss the potential mechanisms by which the Trib proteins preferentially regulate these processes in multiple cell types.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/genetics , Hematopoiesis/genetics , Intracellular Signaling Peptides and Proteins/genetics , Leukemia, Myeloid/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Acute Disease , Animals , Gene Expression Regulation, Leukemic , Humans , Models, Genetic , Protein Serine-Threonine Kinases/genetics , Signal Transduction/genetics
8.
mBio ; 2(4)2011.
Article in English | MEDLINE | ID: mdl-21828218

ABSTRACT

UNLABELLED: Natural killer (NK) cells are equipped to innately produce the cytokine gamma interferon (IFN-γ) in part because they basally express high levels of the signal transducer and activator of transcription 4 (STAT4). Type 1 interferons (IFNs) have the potential to activate STAT4 and promote IFN-γ expression, but concurrent induction of elevated STAT1 negatively regulates access to the pathway. As a consequence, it has been difficult to detect type 1 IFN stimulation of NK cell IFN-γ during viral infections in the presence of STAT1 and to understand the evolutionary advantage for maintaining the pathway. The studies reported here evaluated NK cell responses following infections with lymphocytic choriomeningitis virus (LCMV) in the compartment handling the earliest events after infection, the peritoneal cavity. The production of type 1 IFNs, both IFN-α and IFN-ß, was shown to be early and of short duration, peaking at 30 h after challenge. NK cell IFN-γ expression was detected with overlapping kinetics and required activating signals delivered through type 1 IFN receptors and STAT4. It took place under conditions of high STAT4 levels but preceded elevated STAT1 expression in NK cells. The IFN-γ response reduced viral burdens. Interestingly, increases in STAT1 were delayed in NK cells compared to other peritoneal exudate cell (PEC) populations. Taken together, the studies demonstrate a novel mechanism for stimulating IFN-γ production and elucidate a biological role for type 1 IFN access to STAT4 in NK cells. IMPORTANCE: Pathways regulating the complex and sometimes paradoxical effects of cytokines are poorly understood. Accumulating evidence indicates that the biological consequences of type 1 interferon (IFN) exposure are shaped by modifying the concentrations of particular STATs to change access to the different signaling molecules. The results of the experiments presented conclusively demonstrate that NK cell IFN-γ can be induced through type 1 IFN and STAT4 at the first site of infection during a period with high STAT4 but prior to induction of elevated STAT1 in the cells. The response mediates a role in viral defense. Thus, a very early pathway to and source of IFN-γ in evolving immune responses to infections are identified by this work. The information obtained helps resolve long-standing controversies and advances the understanding of mechanisms regulating key type 1 IFN functions, in different cells and compartments and at different times of infection, for accessing biologically important functions.


Subject(s)
Interferon Type I/immunology , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Killer Cells, Natural/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic choriomeningitis virus/immunology , Animals , Humans , Interferon Type I/biosynthesis , Interleukin-18/immunology , Interleukin-18/metabolism , Lymphocytic Choriomeningitis/pathology , Lymphocytic Choriomeningitis/prevention & control , Mice , Mice, Inbred C57BL
9.
Vaccine ; 28(2): 352-60, 2009 Dec 11.
Article in English | MEDLINE | ID: mdl-19879224

ABSTRACT

The capacity of immune complexes to augment antibody (Ab) responses is well established. The enhancing effects of immune complexes have been attributed mainly to Fc-mediated adjuvant activity, while the ability of Abs to induce antigenic alterations of specific epitopes as a result of immune complex formation has been less well studied. Previously we have shown that the interaction of anti-CD4-binding site (CD4bs) Abs with HIV-1 gp120 induces conformation changes that lead to enhanced antigenicity and immunogenicity of neutralizing epitopes in the V3 loop. The present study shows that significant increases in the antigenicity of the V3 and C1 regions of gp120 were attained for several subtype B gp120s and a subtype C gp120 upon immune complex formation with the anti-CD4bs monoclonal Ab (mAb) 654-D. Such enhancement was observed with immune complexes made with other anti-CD4bs mAbs and anti-V2 mAbs, but not with anti-C2 mAbs, indicating this activity is determined by antigen specificity of the mAb that formed the immune complex. When immune complexes of gp120(LAI)/654-D and gp120(JRFL)/654-D were tested as immunogens in mice, serum Abs to gp120 and V3 were generated at significantly higher titers than those induced by the respective uncomplexed gp120s. Notably, the anti-V3 Ab responses had distinct fine specificities; gp120(JRFL)/654-D stimulated more cross-reactive anti-V3 Abs than gp120(LAI)/654-D. Neutralizing activities against viruses with heterologous envelope were also detected in sera of mice immunized with gp120(JRFL)/654-D, although the neutralization breadth was still limited. Overall this study shows the potential use of gp120/Ab complexes to augment the immunogenicity of HIV-1 envelope gp120, but further improvements are needed to elicit virus-neutralizing Ab responses with higher potency and breadth.


Subject(s)
AIDS Vaccines/immunology , Antibody Formation/immunology , Antigen-Antibody Complex/immunology , Epitopes/immunology , HIV Envelope Protein gp120/immunology , Animals , Antibodies, Monoclonal/immunology , Antibody Specificity/immunology , Female , Mice , Mice, Inbred BALB C
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