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2.
Life Sci Alliance ; 2(3)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097471

RESUMO

A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely unknown. Here, we show that miR-155 regulates the early expansion of B-blasts and later on the survival and proliferation of plasmablasts in a B-cell-intrinsic manner, by tracking antigen-specific B cells in vivo since the onset of antigen stimulation. In agreement, comparative analysis of the transcriptome of miR-155-sufficient and miR-155-deficient plasmablasts at the peak of the response showed that the main processes regulated by miR-155 were DNA metabolic process, DNA replication, and cell cycle. Thus, miR-155 controls the extent of the extrafollicular response by regulating the survival and proliferation of B-blasts, plasmablasts and, consequently, antibody production.


Assuntos
Subpopulações de Linfócitos B/metabolismo , MicroRNAs/genética , Plasmócitos/metabolismo , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Biomarcadores , Proliferação de Células , Sobrevivência Celular/genética , Imunofenotipagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Plasmócitos/imunologia
3.
Nat Commun ; 9(1): 4186, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305631

RESUMO

The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Surprisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ácidos Graxos/metabolismo , Proteína Cofatora de Membrana/metabolismo , Receptores de Complemento/metabolismo , Comunicação Autócrina , Linfócitos T CD4-Positivos/imunologia , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/patologia , Humanos , Ativação Linfocitária/imunologia , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia
5.
Mol Immunol ; 89: 2-9, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28601357

RESUMO

The complement system was defined over a century ago based on its ability to "complement" the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that "local" tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Citoplasma/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Animais , Proteínas do Sistema Complemento/metabolismo , Citoplasma/metabolismo , Humanos , Imunidade Celular/imunologia , Imunidade Inata/imunologia , Modelos Imunológicos , Linfócitos T/metabolismo
6.
Science ; 352(6292): aad1210, 2016 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-27313051

RESUMO

The NLRP3 inflammasome controls interleukin-1ß maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1ß secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas de Transporte/metabolismo , Complemento C5a/imunologia , Inflamassomos/imunologia , Interferon gama/biossíntese , Células Th1/imunologia , Imunidade Adaptativa , Animais , Comunicação Autócrina , Proteínas de Transporte/genética , Ativação do Complemento , Síndromes Periódicas Associadas à Criopirina/imunologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Imunidade Inata , Inflamação/imunologia , Proteína Cofatora de Membrana/imunologia , Camundongos , Camundongos Mutantes , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio/metabolismo , Receptor da Anafilatoxina C5a/agonistas , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/metabolismo , Receptores de Antígenos de Linfócitos T/agonistas , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Quimiocinas/agonistas , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo
7.
Eur J Immunol ; 46(7): 1563-73, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27184294

RESUMO

The inflammasomes are intracellular multiprotein complexes that induce and regulate the generation of the key pro-inflammatory cytokines IL-1ß and IL-18 in response to infectious microbes and cellular stress. The activation of inflammasomes involves several upstream signals including classic pattern or danger recognition systems such as the TLRs. Recently, however, the activation of complement receptors, such as the anaphylatoxin C3a and C5a receptors and the complement regulator CD46, in conjunction with the sensing of cell metabolic changes, for instance increased amino acid influx and glycolysis (via mTORC1), have emerged as additional critical activators of the inflammasome. This review summarizes recent advances in our knowledge about complement-mediated inflammasome activation, with a specific focus on a novel "complement - metabolism - NLRP3 inflammasome axis."


Assuntos
Proteínas do Sistema Complemento/imunologia , Metabolismo Energético , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Inflamassomos/metabolismo , Animais , Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunomodulação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais
8.
J Clin Invest ; 126(1): 377-88, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26657861

RESUMO

The production of high-affinity antibodies by B cells is essential for pathogen clearance. Antibody affinity for antigen is increased through the affinity maturation in germinal centers (GCs). This is an iterative process in which B cells cycle between proliferation coupled with the acquisition of mutations and antigen-based positive selection, resulting in retention of the highest-affinity B cell clones. The posttranscriptional regulator microRNA-155 (miR-155) is critical for efficient affinity maturation and the maintenance of the GCs; however, the cellular and molecular mechanism by which miR-155 regulates GC responses is not well understood. Here, we utilized a miR-155 reporter mouse strain and showed that miR-155 is coexpressed with the proto-oncogene encoding c-MYC in positively selected B cells. Functionally, miR-155 protected positively selected c-MYC+ B cells from apoptosis, allowing clonal expansion of this population, providing an explanation as to why Mir155 deletion impairs affinity maturation and promotes the premature collapse of GCs. We determined that miR-155 directly inhibits the Jumonji family member JARID2, which enhances B cell apoptosis when overexpressed, and thereby promotes GC B cell survival. Our findings also suggest that there is cooperation between c-MYC and miR-155 during the normal GC response, a cooperation that may explain how c-MYC and miR-155 can collaboratively function as oncogenes.


Assuntos
Apoptose , Linfócitos B/fisiologia , MicroRNAs/fisiologia , Proteínas Proto-Oncogênicas c-myc/análise , Animais , Sobrevivência Celular , Centro Germinativo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/análise , Complexo Repressor Polycomb 2/fisiologia
9.
Immunity ; 42(6): 1033-47, 2015 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-26084023

RESUMO

Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4(+) T cell effector function.


Assuntos
Proteínas do Sistema Complemento/imunologia , Síndrome Hemolítico-Urêmica/imunologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Proteína Cofatora de Membrana/metabolismo , Células Th1/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Reprogramação Celular/imunologia , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Proteínas de Homeodomínio/metabolismo , Humanos , Imunidade Celular/genética , Interferon gama/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteína Cofatora de Membrana/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Complexos Multiproteicos/metabolismo , Neuropeptídeos/metabolismo , Fosforilação Oxidativa , RNA Interferente Pequeno/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima
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