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1.
Immunity ; 47(5): 928-942.e7, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29166590

RESUMO

Pancreatic-islet inflammation contributes to the failure of ß cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1ß, and palmitate). IL-33 promoted ß cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the ß cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute ß cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.


Assuntos
Insulina/metabolismo , Interleucina-33/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Células Mieloides/metabolismo , Tretinoína/metabolismo , Animais , Humanos , Inflamação/imunologia , Secreção de Insulina , Interleucina-33/biossíntese , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Linfócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vitamina A/fisiologia
2.
Int J Cancer ; 135(5): 1153-64, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24500882

RESUMO

Adoptive T cell therapy is an important additional treatment option for malignant diseases resistant to chemotherapy. Using a murine high-grade B cell lymphoma model, we have addressed the question whether the B cell differentiation antigen CD19 can act as rejection antigen. CD19(-/-) mice inoculated with CD19(+) B cell lymphoma cells showed higher survival rates than WT mice and were protected against additional tumor challenge. T cell depletion prior to tumor transfer completely abolished the protective response. By heterotypic vaccination of CD19(-/-) mice against murine CD19, survival after tumor challenge was significantly increased. To define protective epitopes within the CD19 molecule, T cells collected from mice that had survived the tumor transfer were analyzed for IFNγ secretion in response to CD19-derived peptides. The majority of mice exhibited a CD4(+) T cell response to CD19 peptide 27, which was the most dominant epitope after CD19 vaccination. A peptide 27-specific CD4(+) T cell line protected CD19(-/-) mice against challenge with CD19(+) lymphoma and also cured a significant proportion of WT mice from recurrent disease in a model of minimal residual disease after chemotherapy. In conclusion, our data highlight CD19-specific CD4(+) T cells for adoptive T cell therapy of B cell lymphomas.


Assuntos
Antígenos CD19/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Animais , Antígenos CD19/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Depleção Linfocítica , Linfoma de Células B/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Células Tumorais Cultivadas
3.
Mucosal Immunol ; 14(6): 1323-1334, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34341503

RESUMO

Innate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.


Assuntos
Suscetibilidade a Doenças , Imunidade Inata , Imunomodulação , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Biomarcadores , Transplante de Medula Óssea , Colite/etiologia , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/deficiência , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Quimeras de Transplante
4.
Sci Signal ; 14(682)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975980

RESUMO

Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal-regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell-specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence of Raf-1 and B-Raf was mediated by multiple RAF-independent pathways, with phosphoinositide 3-kinase (PI3K) playing an important role. Furthermore, we found that ERK phosphorylation strongly increased during the transition from activated B cells to pre-plasmablasts. This increase in ERK phosphorylation did not occur in B cells lacking both Raf-1 and B-Raf, which most likely explains the partial block of plasma cell differentiation in mice lacking both RAFs. Collectively, our data indicate that B-Raf and Raf-1 are not necessary to mediate ERK phosphorylation in naïve or activated B cells but are essential for mediating the marked increase in ERK phosphorylation during the transition from activated B cells to pre-plasmablasts.


Assuntos
Linfócitos B/citologia , MAP Quinases Reguladas por Sinal Extracelular , Plasmócitos/citologia , Proteínas Proto-Oncogênicas c-raf , Animais , Diferenciação Celular , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases , Fosforilação , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo
5.
Blood Adv ; 1(27): 2679-2691, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29296921

RESUMO

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. Although their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines interleukin 12 (IL-12) and IL-15, and correlates with expression of the master transcription factor of cytotoxicity, eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56, and CD16 among other NK-cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells with perforin and granzymes. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines.

6.
PLoS One ; 8(10): e77375, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24130880

RESUMO

Over-expression of the proto-oncogene c-MYC is frequently observed in a variety of tumors and is a hallmark of Burkitt´s lymphoma. The fact that many tumors are oncogene-addicted to c-MYC, renders c-MYC a powerful target for anti-tumor therapy. Using a xenogenic vaccination strategy by immunizing C57BL/6 mice with human c-MYC protein or non-homologous peptides, we show that the human c-MYC protein, despite its high homology between mouse and man, contains several immunogenic epitopes presented in the context of murine H2(b) haplotype. We identified an MHC class II-restricted CD4⁺ T-cell epitope and therein an MHC class I-restricted CD8⁺ T-cell epitope (SSPQGSPEPL) that, after prime/boost immunization, protected up to 25% of mice against a lethal lymphoma challenge. Lymphoma-rejecting animals contained MHC multimer-binding CD8⁺ cell within the peripheral blood and displayed in vivo cytolytic activity with specificity for SSPQGSPEPL. Taken together these data suggest that oncogenic c-MYC can be targeted with specific T-cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Linfoma/prevenção & controle , Proteínas Proto-Oncogênicas c-myc/imunologia , Sequência de Aminoácidos , Animais , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/química , Humanos , Interferon gama/imunologia , Linfoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/química , Vacinação
7.
PLoS One ; 7(3): e34552, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22479645

RESUMO

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60-70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80-100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches.


Assuntos
Antígenos/imunologia , Interferon gama/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Animais , Antígenos/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Galinhas , Regulação Neoplásica da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Humanos , Linfoma de Células B/genética , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/genética , Ovalbumina/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Transdução de Sinais
8.
PLoS One ; 7(7): e42021, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22860051

RESUMO

BACKGROUND: A given tumor is usually dependent on the oncogene that is activated in the respective tumor entity. This phenomenon called oncogene addiction provides the rationale for attempts to target oncogene products in a therapeutic manner, be it by small molecules, by small interfering RNAs (siRNA) or by antigen-specific T cells. As the proto-oncogene product is required also for the function of normal cells, this raises the question whether there is a therapeutic window between the adverse effects of specific inhibitors or T cells to normal tissue that may limit their application, and their beneficial tumor-specific therapeutic action. To address this crucial question, suitable mouse strains need to be developed, that enable expression of the human proto-oncogene not only in tumor but also in normal cells. The aim of this work is to provide such a mouse strain for the human proto-oncogene product c-MYC. PRINCIPAL FINDINGS: We generated C57BL/6-derived embryonic stem cells that are transgenic for a humanized c-Myc gene and established a mouse strain (hc-Myc) that expresses human c-MYC instead of the murine ortholog. These transgenic animals harbor the humanized c-Myc gene integrated into the endogenous murine c-Myc locus. Despite the lack of the endogenous murine c-Myc gene, homozygous mice show a normal phenotype indicating that human c-MYC can replace its murine ortholog. CONCLUSIONS: The newly established hc-Myc mouse strain provides a model system to study in detail the adverse effects of therapies that target the human c-MYC protein. To mimic the clinical situation, hc-Myc mice may be cross-bred to mice that develop tumors due to overexpression of human c-MYC. With these double transgenic mice it will be possible to study simultaneously the therapeutic efficiency and adverse side effects of MYC-specific therapies in the same mouse.


Assuntos
Genes myc , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Southern Blotting , Células-Tronco Embrionárias , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Reação em Cadeia da Polimerase , Proto-Oncogene Mas
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