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1.
Blood ; 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32530039

RESUMO

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the five-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. Based on these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

2.
Blood ; 134(2): 147-159, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31015190

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1 -/-) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ-neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ-dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1 -/- mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ-dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.


Assuntos
Linfo-Histiocitose Hemofagocítica/imunologia , Neutrófilos/efeitos dos fármacos , Pirazóis/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
3.
Nature ; 532(7599): 389-93, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27064903

RESUMO

Asymmetric cell division, the partitioning of cellular components in response to polarizing cues during mitosis, has roles in differentiation and development. It is important for the self-renewal of fertilized zygotes in Caenorhabditis elegans and neuroblasts in Drosophila, and in the development of mammalian nervous and digestive systems. T lymphocytes, upon activation by antigen-presenting cells (APCs), can undergo asymmetric cell division, wherein the daughter cell proximal to the APC is more likely to differentiate into an effector-like T cell and the distal daughter is more likely to differentiate into a memory-like T cell. Upon activation and before cell division, expression of the transcription factor c-Myc drives metabolic reprogramming, necessary for the subsequent proliferative burst. Here we find that during the first division of an activated T cell in mice, c-Myc can sort asymmetrically. Asymmetric distribution of amino acid transporters, amino acid content, and activity of mammalian target of rapamycin complex 1 (mTORC1) is correlated with c-Myc expression, and both amino acids and mTORC1 activity sustain the differences in c-Myc expression in one daughter cell compared to the other. Asymmetric c-Myc levels in daughter T cells affect proliferation, metabolism, and differentiation, and these effects are altered by experimental manipulation of mTORC1 activity or c-Myc expression. Therefore, metabolic signalling pathways cooperate with transcription programs to maintain differential cell fates following asymmetric T-cell division.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Divisão Celular , Polaridade Celular , Ativação Linfocitária , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Animais , Diferenciação Celular/genética , Polaridade Celular/genética , Feminino , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética
4.
Immunity ; 44(1): 88-102, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795252

RESUMO

The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic proliferation, but thymic T cell development was unaffected. In contrast, Aif-deficient B cells developed and functioned normally. The difference in the dependency of T cells versus B cells on AIF for function and survival correlated with their metabolic requirements. Ectopic Ndi1 expression rescued homeostatic proliferation of Aif-deficient T cells. Despite its reported roles in cell death, fibroblasts, thymocytes and B cells lacking AIF underwent normal death. These studies suggest that the primary role of AIF relates to complex I function, with differential effects on T and B cells.


Assuntos
Fator de Indução de Apoptose/metabolismo , Linfócitos B/metabolismo , Mitocôndrias/fisiologia , Linfócitos T/metabolismo , Animais , Apoptose , Respiração Celular/fisiologia , Complexo I de Transporte de Elétrons/metabolismo , Fibroblastos/metabolismo , Glicólise/fisiologia , Camundongos , Camundongos Knockout , Camundongos Mutantes
5.
Cell ; 157(5): 1189-202, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24813850

RESUMO

Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1(-/-) mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1(-/-)tnfr1(-/-) mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.


Assuntos
Caspase 8/metabolismo , Genes Letais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Caspase 8/genética , Morte Celular , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Fibroblastos/metabolismo , Inflamação/metabolismo , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo
6.
Cytokine ; 59(3): 467-78, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22704694

RESUMO

An effective immune response to an invading viral pathogen requires the combined actions of both innate and adaptive immune cells. For example, NK cells and cytotoxic CD8 T cells are capable of the direct engagement of infected cells and the mediation of antiviral responses. Both NK and CD8 T cells depend on common gamma chain (γc) cytokine signals for their development and homeostasis. The γc cytokine IL-15 is very well characterized for its role in promoting the development and homeostasis of NK cells and CD8 T cells, but emerging literature suggests that IL-15 mediates the anti-viral responses of these cell populations during an active immune response. Both NK cells and CD8 T cells must become activated, migrate to sites of infection, survive at those sites, and expand in order to maximally exert effector functions, and IL-15 can modulate each of these processes. This review focuses on the functions of IL-15 in the regulation of multiple aspects of NK and CD8 T cell biology, investigates the mechanisms by which IL-15 may exert such diverse functions, and discusses how these different facets of IL-15 biology may be therapeutically exploited to combat viral diseases.


Assuntos
Imunidade/imunologia , Interleucina-15/imunologia , Vírus/imunologia , Animais , Humanos , Linfócitos/imunologia , Viroses/imunologia , Viroses/terapia
7.
PLoS One ; 7(5): e37539, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22624047

RESUMO

Following influenza infection, natural killer (NK) cells function as interim effectors by suppressing viral replication until CD8 T cells are activated, proliferate, and are mobilized within the respiratory tract. Thus, NK cells are an important first line of defense against influenza virus. Here, in a murine model of influenza, we show that virally-induced IL-15 facilitates the trafficking of NK cells into the lung airways. Blocking IL-15 delays NK cell entry to the site of infection and results in a disregulated control of early viral replication. By the same principle, viral control by NK cells can be therapeutically enhanced via intranasal administration of exogenous IL-15 in the early days post influenza infection. In addition to controlling early viral replication, this IL-15-induced mobilization of NK cells to the lung airways has important downstream consequences on adaptive responses. Primarily, depletion of responding NK1.1+ NK cells is associated with reduced immigration of influenza-specific CD8 T cells to the site of infection. Together this work suggests that local deposits of IL-15 in the lung airways regulate the coordinated innate and adaptive immune responses to influenza infection and may represent an important point of immune intervention.


Assuntos
Imunidade Inata/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Sistema Respiratório/imunologia , Animais , Lavagem Broncoalveolar , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Citometria de Fluxo , Interleucina-15/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Sistema Respiratório/virologia
8.
Semin Immunol ; 24(6): 399-404, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23313070

RESUMO

As T cells respond to pathogens, they must transition from a quiescent, naïve state, to a rapidly proliferating, active effector state, and back again to a quiescent state as they develop into memory cells. Such transitions place unique metabolic demands on the differentiating cells. T cells meet these demands by altering their metabolic profiles, which are, in turn, regulated by distinct signaling cascades and transcriptional programs. Here, we examine the metabolic profiles of T cells during an acute immune response and discuss the signal and transcriptional regulators of these metabolic changes.


Assuntos
Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Linfócitos T , Diferenciação Celular , Humanos , Memória Imunológica , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
J Immunol ; 186(12): 6667-71, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21572025

RESUMO

Effective vaccines against intracellular pathogens rely on the generation and maintenance of memory CD8 T cells (T(mem)). Hitherto, evidence has indicated that CD8 T(mem) use the common γ-chain cytokine IL-15 for their steady-state maintenance in the absence of Ag. This evidence, however, has been amassed predominantly from models of acute, systemic infections. Given that the route of infection can have significant impact on the quantity and quality of the resultant T(mem), reliance on limited models of infection may restrict our understanding of long-term CD8 T(mem) survival. In this article, we show IL-15-independent generation, maintenance, and function of CD8 T(mem) after respiratory infection with influenza virus. Importantly, we demonstrate that alternating between mucosal and systemic deliveries of the identical virus prompts this change in IL-15 dependence, necessitating a re-evaluation of the current model of CD8 T(mem) maintenance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-15/imunologia , Membrana Mucosa/imunologia , Humanos , Influenza Humana/imunologia , Orthomyxoviridae/imunologia
10.
J Immunol ; 186(1): 174-82, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21098221

RESUMO

The cytokines generated locally in response to infection play an important role in CD8 T cell trafficking, survival, and effector function, rendering these signals prime candidates for immune intervention. In this paper, we show that localized increases in the homeostatic cytokine IL-15 induced by influenza infection is responsible for the migration of CD8 effector T cells to the site of infection. Moreover, intranasal delivery of IL-15-IL-15Rα soluble complexes (IL-15c) specifically restores the frequency of effector T cells lost in the lung airways of IL-15-deficient animals after influenza infection. Exogenous IL-15c quantitatively augments the respiratory CD8 T cell response, and continued administration of IL-15c throughout the contraction phase of the anti-influenza CD8 T cell response magnifies the resultant CD8 T cell memory generated in situ. This treatment extends the ability of these cells to protect against heterologous infection, immunity that typically depreciates over time. Overall, our studies describe what to our knowledge is a new function for IL-15 in attracting effector CD8 T cells to the lung airways and suggest that adjuvanting IL-15 could be used to prolong anti-influenza CD8 T cell responses at mucosal surfaces to facilitate pathogen elimination.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Movimento Celular/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Interleucina-15/fisiologia , Pulmão/imunologia , Pulmão/virologia , Infecções por Orthomyxoviridae/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/imunologia , Memória Imunológica , Interleucina-15/biossíntese , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/prevenção & controle , Infecções Respiratórias/imunologia , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/virologia
11.
Biochem J ; 429(3): 485-95, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20497125

RESUMO

Acidocalcisomes are acidic calcium-storage compartments described from bacteria to humans and characterized by their high content in poly P (polyphosphate), a linear polymer of many tens to hundreds of Pi residues linked by high-energy phosphoanhydride bonds. In the present paper we report that millimolar levels of short-chain poly P (in terms of Pi residues) and inorganic PPi are present in sea urchin extracts as detected using 31P-NMR, enzymatic determinations and agarose gel electrophoresis. Poly P was localized to granules randomly distributed in the sea urchin eggs, as shown by labelling with the poly-P-binding domain of Escherichia coli exopolyphosphatase. These granules were enriched using iodixanol centrifugation and shown to be acidic and to contain poly P, as determined by Acridine Orange and DAPI (4',6'-diamidino-2-phenylindole) staining respectively. These granules also contained large amounts of calcium, sodium, magnesium, potassium and zinc, as detected by X-ray microanalysis, and bafilomycin A1-sensitive ATPase, pyrophosphatase and exopolyphosphatase activities, as well as Ca2+/H+ and Na+/H+ exchange activities, being therefore similar to acidocalcisomes described in other organisms. Calcium release from these granules induced by nigericin was associated with poly P hydrolysis. Although NAADP (nicotinic acid-adenine dinucleotide phosphate) released calcium from the granule fraction, this activity was not significantly enriched as compared with the NAADP-stimulated calcium release from homogenates and was not accompanied by poly P hydrolysis. GPN (glycyl-L-phenylalanine-naphthylamide) released calcium when added to sea urchin homogenates, but was unable to release calcium from acidocalcisome-enriched fractions, suggesting that these acidic stores are not the targets for NAADP.


Assuntos
Cálcio/metabolismo , Grânulos Citoplasmáticos/metabolismo , NADP/análogos & derivados , Óvulo/metabolismo , Polifosfatos/metabolismo , Ácidos/metabolismo , Animais , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , NADP/metabolismo , Óvulo/ultraestrutura , Ouriços-do-Mar
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