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1.
J Immunol ; 213(3): 384-393, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38864663

RESUMEN

Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.


Asunto(s)
Células Dendríticas , Estrés del Retículo Endoplásmico , Endorribonucleasas , Enfermedad Injerto contra Huésped , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Ratones , Estrés del Retículo Endoplásmico/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Endorribonucleasas/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Trasplante de Células Madre Hematopoyéticas , Trasplante de Médula Ósea , Transducción de Señal , Diferenciación Celular/inmunología , Efecto Injerto vs Leucemia/inmunología
2.
J Immunol ; 210(4): 486-495, 2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36548465

RESUMEN

The gastrointestinal (GI) tract is a frequent target organ in acute graft-versus-host disease (aGVHD), which can determine the morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells recognize allogeneic Ags presented by host APCs, proliferate, and differentiate into Th1 and Th17 cells that drive GVHD pathogenesis. IL-12 has been shown to play an important role in amplifying the allogeneic response in preclinical and clinical studies. This study demonstrates that IL-12Rß2 expression on recipient nonhematopoietic cells is required for optimal development of aGVHD in murine models of allo-HCT. aGVHD attenuation by genetic depletion of IL-12R signaling is associated with reduced MHC class II expression by intestinal epithelial cells and maintenance of intestinal integrity. We verified IL-12Rß2 expression on activated T cells and in the GI tract. This study, to our knowledge, reveals a novel function of IL-12Rß2 in GVHD pathogenesis and suggests that selectively targeting IL-12Rß2 on host nonhematopoietic cells may preserve the GI tract after allo-HCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Enfermedad Aguda , Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/genética , Intestinos/patología , Trasplante Homólogo
3.
Blood ; 140(19): 2076-2090, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-35981499

RESUMEN

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine leukemia inhibitory factor (LIF) in protecting against GVHD development. Administrating recombinant LIF protein (rLIF) protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia activity, which is crucial to prevent tumor relapse. We found that rLIF decreases the infiltration and activation of donor immune cells and protects intestinal stem cells to ameliorate GVHD. Mechanistically, rLIF downregulates IL-12-p40 expression in recipient dendritic cells after irradiation through activating STAT1 signaling, which results in decreased major histocompatibility complex II levels on intestinal epithelial cells and decreased donor T-cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising antileukemic efficacy.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Factor Inhibidor de Leucemia , Leucemia , Animales , Ratones , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Factor Inhibidor de Leucemia/genética , Trasplante Homólogo
4.
J Immunol ; 206(1): 59-66, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33268481

RESUMEN

Friend leukemia virus integration 1 (Fli-1) is an ETS transcription factor and a critical regulator of inflammatory mediators, including MCP-1, CCL5, IL-6, G-CSF, CXCL2, and caspase-1. GM-CSF is a regulator of granulocyte and macrophage lineage differentiation and a key player in the pathogenesis of inflammatory/autoimmune diseases. In this study, we demonstrated that Fli-1 regulates the expression of GM-CSF in both T cells and endothelial cells. The expression of GM-CSF was significantly reduced in T cells and endothelial cells when Fli-1 was reduced. We found that Fli-1 binds directly to the GM-CSF promoter using chromatin immunoprecipitation assay. Transient transfection assays indicated that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner, and mutation of the Fli-1 DNA binding domain resulted in a significant loss of transcriptional activation. Mutation of a known phosphorylation site within the Fli-1 protein led to a significant increase in GM-CSF promoter activation. Thus, direct binding to the promoter and phosphorylation are two important mechanisms behind Fli-1-driven activation of the GM-CSF promoter. In addition, Fli-1 regulates GM-CSF expression in an additive manner with another transcription factor Sp1. Finally, we demonstrated that a low dose of a chemotherapeutic drug, camptothecin, inhibited expression of Fli-1 and reduced GM-CSF production in human T cells. These results demonstrate novel mechanisms for regulating the expression of GM-CSF and suggest that Fli-1 is a critical druggable regulator of inflammation and immunity.


Asunto(s)
Endotelio/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Linfocitos T/fisiología , Animales , Camptotecina/farmacología , Endotelio/patología , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Células Jurkat , Ratones , Terapia Molecular Dirigida , Células 3T3 NIH , Regiones Promotoras Genéticas/genética , Proteína Proto-Oncogénica c-fli-1/genética , ARN Interferente Pequeño/genética , Factor de Transcripción Sp1/genética , Linfocitos T/efectos de los fármacos , Inhibidores de Topoisomerasa I/farmacología
5.
Blood ; 136(7): 857-870, 2020 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-32403132

RESUMEN

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Linfocitos T CD8-positivos/fisiología , Metabolismo Energético/genética , Activación de Linfocitos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Inmunomodulación/genética , Melanoma Experimental/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos
6.
Am J Transplant ; 21(11): 3538-3549, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33934505

RESUMEN

IL-12 (p35/p40) and IL-23 (p19/p40) signal through IL-12R (IL-12Rß2/ß1) and IL-23R (IL-23Rα/IL-12Rß1), respectively, which can promote pathogenic T lymphocyte activation, differentiation, and function in graft-versus-host disease (GVHD). With the use of murine models of allogeneic hematopoietic cell transplantation (HCT), we found that IL-12Rß1 on donor T cells was dispensable to induce acute GVHD development in certain circumstances, while IL-23Rα was commonly required. This observation challenges the current paradigm regarding IL-12Rß1 as a prerequisite to transmit IL-23 signaling. We hypothesized that p19/EBI3 (IL-39) may have an important role during acute GVHD. With the use of gene transfection and immunoprecipitation approaches, we verified that p19 and EBI3 can form biological heterodimers. We found that IL-39 levels in recipient serum positively correlated with development of acute GVHD in experimental models and in clinical settings, thereby implicating IL-39 in the pathogenesis of acute GVHD. Furthermore, we observed that human T cells can signal in response to IL-39. In chronic GVHD, IL-23Rα and IL-12Rß1 were similarly required for donor T cell pathogenicity, and IL-39 levels were not significantly different from controls without GVHD. Collectively, we identify a novel cytokine, IL-39, as a pathogenic factor in acute GVHD, which represents a novel potential therapeutic target to control GVHD and other inflammatory disorders.


Asunto(s)
Enfermedad Injerto contra Huésped , Interleucinas/inmunología , Receptores de Interleucina/inmunología , Animales , Enfermedad Injerto contra Huésped/etiología , Humanos , Interleucina-12 , Interleucina-23 , Ratones , Linfocitos T , Virulencia
7.
Blood ; 133(3): 266-279, 2019 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-30514750

RESUMEN

Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Sirtuin-1 (Sirt-1) plays a crucial role in various biological processes including cellular senescence, metabolism, and inflammatory responses. Sirt-1 deacetylation regulates different transcription factors that are important for modulating immune responses. In the current study, we addressed the role of Sirt-1 in GVHD induction by employing Sirt-1 conditional knockout mice as well as a pharmacological Sirt-1 inhibitor. Using major histocompatibility complex (MHC)-mismatched and MHC-matched murine BMT models, we found that Sirt-1-/- T cells had a reduced ability to induce acute GVHD (aGVHD) via enhanced p53 acetylation. Sirt-1-deficient T cells also promoted induced regulatory T cell (iTreg) differentiation and inhibited interferon-γ production after allo-BMT. Sirt-1 deletion in iTregs increased Foxp3 stability and restrained iTreg conversion into pathogenic T cells. Furthermore, we found that administration with a Sirt-1 inhibitor, Ex-527, significantly improved recipient survival and clinical scores, with no signs of tumor relapse. These results indicate that Sirt-1 inhibition can attenuate GVHD while preserving the graft-versus-leukemia effect. Consistently, Sirt-1-deficient T cells also displayed a remarkably reduced ability to induce chronic GVHD (cGVHD). Mechanistic studies revealed that Sirt-1 deficiency in T cells enhanced splenic B-cell reconstitution and reduced follicular T helper cell development. Sirt-1 deficiency in T cells modulated donor B-cell responses reducing both B-cell activation and plasma cell differentiation. In addition, therapeutic Sirt-1 inhibition could both prevent cGVHD and reduce established cGVHD. In conclusion, Sirt-1 is a promising therapeutic target for the control of aGVHD and cGVHD pathogenesis and possesses high potential for clinical application.


Asunto(s)
Linfocitos B/inmunología , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Activación de Linfocitos/inmunología , Sirtuina 1/fisiología , Linfocitos T Reguladores/inmunología , Acetilación , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Trasplante de Médula Ósea , Carbazoles/farmacología , Diferenciación Celular , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Efecto Injerto vs Leucemia/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Sirtuina 1/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo , Proteína p53 Supresora de Tumor/metabolismo
8.
Proc Natl Acad Sci U S A ; 115(7): 1582-1587, 2018 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-29382747

RESUMEN

Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).


Asunto(s)
Diferenciación Celular , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Janus Quinasa 2/fisiología , Mielofibrosis Primaria/inmunología , Linfocitos T/inmunología , Células Th2/inmunología , Animales , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/genética , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/prevención & control , Trasplante de Piel , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Biol Chem ; 294(23): 9198-9212, 2019 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-30971427

RESUMEN

Adoptive transfer of tumor epitope-reactive T cells has emerged as a promising strategy to control tumor growth. However, chronically-stimulated T cells expanded for adoptive cell transfer are susceptible to cell death in an oxidative tumor microenvironment. Because oxidation of cell-surface thiols also alters protein functionality, we hypothesized that increasing the levels of thioredoxin (Trx), an antioxidant molecule facilitating reduction of proteins through cysteine thiol-disulfide exchange, in T cells will promote their sustained antitumor function. Using pre-melanosome protein (Pmel)-Trx1 transgenic mouse-derived splenic T cells, flow cytometry, and gene expression analysis, we observed here that higher Trx expression inversely correlated with reactive oxygen species and susceptibility to T-cell receptor restimulation or oxidation-mediated cell death. These Trx1-overexpressing T cells exhibited a cluster of differentiation 62Lhi (CD62Lhi) central memory-like phenotype with reduced glucose uptake (2-NBDGlo) and decreased effector function (interferon γlo). Furthermore, culturing tumor-reactive T cells in the presence of recombinant Trx increased the dependence of T cells on mitochondrial metabolism and improved tumor control. We conclude that strategies for increasing the antioxidant capacity of antitumor T cells modulate their immunometabolic phenotype leading to improved immunotherapeutic control of established tumors.


Asunto(s)
Linfocitos T/metabolismo , Tiorredoxinas/metabolismo , Animales , Antioxidantes/metabolismo , Línea Celular Tumoral , Transportador de Glucosa de Tipo 1/metabolismo , Selectina L/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Estrés Oxidativo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Linfocitos T/citología , Linfocitos T/inmunología , Tiorredoxinas/genética , Microambiente Tumoral , Antígeno gp100 del Melanoma/genética , Antígeno gp100 del Melanoma/metabolismo
10.
Blood ; 131(17): 1974-1986, 2018 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-29530952

RESUMEN

Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17-92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.


Asunto(s)
Bronquiolitis Obliterante/inmunología , Enfermedad Injerto contra Huésped/inmunología , MicroARNs/inmunología , Células Plasmáticas/inmunología , Esclerodermia Difusa/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Formación de Anticuerpos/genética , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Bronquiolitis Obliterante/genética , Bronquiolitis Obliterante/patología , Modelos Animales de Enfermedad , Centro Germinal/inmunología , Centro Germinal/patología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Activación de Linfocitos/genética , Ratones , Ratones Noqueados , MicroARNs/genética , Células Plasmáticas/patología , Esclerodermia Difusa/genética , Esclerodermia Difusa/patología , Células TH1/patología , Células Th17/patología
11.
J Immunol ; 201(9): 2812-2823, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30242073

RESUMEN

CD8+ induced regulatory T cells (iTregs) have been identified to suppress alloreactive immune responses and expressed regulatory T cell (Treg) ontological markers as similar as CD4+ iTregs. However, adoptive transfer of CD8+ iTreg-based therapy is hampered by the instability of Treg specific-transcription factor, Foxp3. As CD8+ iTregs were previously demonstrated to possess superior tumor-killing ability to CD4+ iTregs, adoptive transfer of stabilized CD8+ iTregs would be a potential therapy to prevent tumor relapse during graft-versus-leukemia disease (GVHD) treatment. In the current study, we generated alloantigen reactive CD8+ iTregs from JAK2-/- T cells and adoptively transferred them to MHC-mismatched and haploidentical murine models of allogeneic bone marrow transplantation. JAK2-/- CD8+ iTregs not only attenuated GVHD but also preserved graft-versus-leukemia effect. Mechanistic analysis revealed that JAK2-/- CD8+ iTregs upregulated natural Treg marker (neuropilin-1), and augmented DNA demethylation of CNS2 region within Foxp3 gene. These properties licensed JAK2-/- CD8+ iTregs to retain high Foxp3 expression resulting in less conversion to type 1 CTLs; as a result, JAK2-/- CD8+ iTregs were able to maintain their suppressive and cytolytic function. Thus, our findings provide a strong rationale and means to stabilize CD8+ iTregs by targeting JAK2, and the stabilized CD8+ iTregs exhibit therapeutic potential for alleviating GVHD and preserving the graft-versus-leukemia effect.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Factores de Transcripción Forkhead/inmunología , Efecto Injerto vs Leucemia/inmunología , Janus Quinasa 2/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Janus Quinasa 2/farmacocinética , Ratones , Linfocitos T Reguladores/inmunología
12.
Blood ; 130(2): 146-155, 2017 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-28550044

RESUMEN

Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression. In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, overexpression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction. HDAC11KO T cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-γ, tumor necrosis factor, and EOMES. In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Enfermedad Injerto contra Huésped/inmunología , Histona Desacetilasa 1/genética , Linfoma de Células B/inmunología , Proteínas de Dominio T Box/genética , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Cromatina/química , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Histona Desacetilasa 1/deficiencia , Histona Desacetilasa 1/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Activación de Linfocitos , Linfoma de Células B/genética , Linfoma de Células B/patología , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Transducción de Señal , Proteínas de Dominio T Box/inmunología , Linfocitos T/patología , Linfocitos T/trasplante , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
13.
J Immunol ; 196(7): 3168-79, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26903480

RESUMEN

Beyond its critical role in T cells, T-bet regulates the functions of APCs including dendritic cells and B cells, as well as NK cells. Given that recipient APCs are essential for priming allogeneic T cells and recipient NK or T cells are able to reject allogeneic donor cells, we evaluated the role of T-bet on the host in acute graft-versus-host disease (GVHD) using murine models of allogeneic bone marrow transplantation. T-bet(-/-) recipients developed significantly milder GVHD than their wild type counterparts in MHC-mismatched or CD4-dependent minor histocompatibility Ag-mismatched models. Allogeneic donor T cells, in particular, CD4 subset, significantly reduced IFN-γ production, proliferation and migration, and caused less injury in liver and gut of T-bet(-/-) recipients. We further observed that T-bet on recipient hematopoietic cells was primarily responsible for the donor T cell response and pathogenicity in GVHD. T-bet(-/-) dendritic cells expressed higher levels of Trail, whereas they produced lower levels of IFN-γ and IL-12/23 p40, as well as chemokine CXCL9, resulting in significantly higher levels of apoptosis, less priming, and infiltration of donor T cells. Meanwhile, NK cells in T-bet(-/-) hosts partially contribute to the decreased donor T cell proliferation. Furthermore, although T-bet on hematopoietic cells was required for GVHD development, it was largely dispensable for the graft-versus-leukemia effect. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of GVHD through regulating donor T cells and recipient hematopoietic cells.


Asunto(s)
Células de la Médula Ósea/metabolismo , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Enfermedad Aguda , Animales , Trasplante de Médula Ósea , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Efecto Injerto vs Leucemia/genética , Efecto Injerto vs Leucemia/inmunología , Interferón gamma/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Bazo/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Donantes de Tejidos , Trasplante Homólogo
14.
Blood ; 126(11): 1314-23, 2015 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-26138686

RESUMEN

MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Leucemia Experimental/inmunología , MicroARNs/genética , MicroARNs/inmunología , Linfocitos T/inmunología , Aloinjertos , Animales , Trasplante de Médula Ósea , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia/genética , Efecto Injerto vs Leucemia/inmunología , Interferón gamma/biosíntesis , Leucemia Experimental/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , MicroARNs/antagonistas & inhibidores , Oligonucleótidos/farmacología
16.
J Immunol ; 195(2): 717-25, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26048147

RESUMEN

Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent→F1, and miHAg-mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY-iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect.


Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/prevención & control , Antígeno H-Y/inmunología , Leucemia/terapia , Linfocitos T Reguladores/inmunología , Animales , Proliferación Celular , Femenino , Expresión Génica , Efecto Injerto vs Leucemia , Antígeno H-Y/genética , Prueba de Histocompatibilidad , Leucemia/genética , Leucemia/inmunología , Leucemia/mortalidad , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores Sexuales , Análisis de Supervivencia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/trasplante , Trasplante Homólogo , Irradiación Corporal Total
17.
J Immunol ; 194(1): 388-97, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25404360

RESUMEN

T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T cell responses in acute graft-versus-host disease (GVHD) and found that T-bet(-/-) T cells induced significantly less GVHD compared with wild-type or IFN-γ(-/-) counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet(-/-), but not IFN-γ(-/-), CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet(-/-) T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ, such as CXCR3 and programmed death-1, or systematic IFN-γ, such as NKG2D, I-A(b), and granzyme B. Although both T-bet(-/-) and IFN-γ(-/-) CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet(-/-) T cells had a compromised graft-versus-leukemia effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Interferón gamma/genética , Proteínas de Dominio T Box/genética , Células TH1/inmunología , Células Th17/inmunología , Animales , Diferenciación Celular/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Regulación de la Expresión Génica/inmunología , Granzimas/biosíntesis , Antígenos de Histocompatibilidad Clase II/biosíntesis , Interleucina-17/antagonistas & inhibidores , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/biosíntesis , Receptor de Muerte Celular Programada 1/biosíntesis , ARN Mensajero/genética , Receptores CXCR3/biosíntesis , Receptores de Interferón/biosíntesis , Receptores de Interferón/genética , Células TH1/citología , Células Th17/citología , Receptor de Interferón gamma
18.
Cancer Immunol Immunother ; 65(3): 247-59, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26825102

RESUMEN

Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported that adoptively transferred CD4+ and CD8+ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ(+)Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues--such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)--can be exploited to bolster the therapeutic potential of IL-17(+) lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-17/biosíntesis , Neoplasias/terapia , Humanos , Memoria Inmunológica , Inmunoterapia , Proteína Coestimuladora de Linfocitos T Inducibles/fisiología , Interleucina-12/fisiología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Células Th17/fisiología
19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 38(2): 140-3, 2016 Apr.
Artículo en Zh | MEDLINE | ID: mdl-27181888

RESUMEN

OBJECTIVE: To investigate the effect of atrial fibrillation on the accuracy of parameters monitored by transpulmonary thermodilution method. METHODS: Totally 12 patients from emergency intensive care unit with paroxysmal atrial fibrillation were enrolled. The hemodynamic parameters such as heart rate, mean arterial pressure, cardiac index, systemic vascular resistance index, intrathoracic blood volume index, and extravascular lung water index were monitored by transpulmonary thermodilution method before paroxysmal atrial fibrillation and during atrial fibrillation, the number of B-lines was detected by lung ultrasonography before and during paroxysmal atrial fibrillation. The changes of all the parameters were analyzed. RESULTS: When the paroxysmal atrial fibrillation happened, the heart rate increased significantly [(123.3±20.0) beat/min vs. (98.9±12.3) beat/min, P=0.006]; the mean arterial pressure [(86.9±10.2) mmHg vs. (93.0±12.5) mmHg, P=0.058], cardiac index [(2.82±0.62) L/(min·m(2)) vs. (3.31±1.02) L/(min·m(2)), P=0.058] and systemic vascular resistance index [(2254±947) dyn·s·cm(-5)·m(2) vs. (2302±828) dyn·s·cm(-5)·m(2), P=0.351] had no obvious change; however, the intrathoracic blood volume index significantly increased [(1333±90) ml/m(2) vs. (937±111) ml/m(2), P<0.001]; extravascular lung water index also increased significantly [(16.1±1.1) ml/kg vs. (6.5±1.9) ml/kg, P<0.001]. No significant difference was found in the number of B-lines detected by lung ultrasonography before and during atrial fibrillation (10.0±4.2 vs. 9.4±4.4, P=0.180). CONCLUSION: Both intrathoracic blood volume and extravascular lung water monitored by transpulmonary thermodilution method were overvalued during paroxysmal atrial fibrillation, which may mislead the clinical judgment and decision-making.


Asunto(s)
Fibrilación Atrial/fisiopatología , Volumen Sanguíneo , Agua Pulmonar Extravascular , Termodilución , Presión Sanguínea , Gasto Cardíaco , Frecuencia Cardíaca , Hemodinámica , Humanos , Unidades de Cuidados Intensivos , Resistencia Vascular
20.
Biol Blood Marrow Transplant ; 21(7): 1195-204, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25846718

RESUMEN

Graft-versus-host disease (GVHD), in both its acute (aGVHD) and chronic (cGVHD) forms, remains a major obstacle impeding successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells, in particular pathogenic T helper (Th) 1 and Th17 subsets, are a driving force for the induction of GVHD. IL-12 and IL-23 cytokines share a common p40 subunit and play a critical role in driving Th1 differentiation and in stabilizing the Th17 phenotype, respectively. In our current study, we hypothesized that p40 is an essential cytokine in the development of GVHD. By using p40-deficient mice, we found that both donor- and host-derived p40 contribute to the development of aGVHD. Neutralization of p40 with an anti-p40 mAb inhibited Th1- and Th17-polarization in vitro. Furthermore, anti-p40 treatment reduced aGVHD severity while preserving the graft-versus-leukemia (GVL) activity. Alleviation of aGVHD was associated with an increase of Th2 differentiation and a decrease of Th1 and Th17 effector T cells in the GVHD target organs. In addition, anti-p40 treatment attenuated the severity of sclerodermatous cGVHD. These results provide a strong rationale that blockade of p40 may represent a promising therapeutic strategy in preventing and treating aGVHD and cGVHD while sparing the GVL effect after allo-HSCT.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/terapia , Subunidad p40 de la Interleucina-12/inmunología , Leucemia Mieloide Aguda/terapia , Linfoma de Células B/terapia , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Expresión Génica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia , Prueba de Histocompatibilidad , Humanos , Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Depleción Linfocítica , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Cultivo Primario de Células , Células TH1/inmunología , Células TH1/patología , Células Th17/inmunología , Células Th17/patología , Células Th2/inmunología , Células Th2/patología , Trasplante Homólogo
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