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1.
Immunity ; 49(4): 695-708.e4, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30291027

RESUMO

B cells can present antigens to CD4+ T cells, but it is thought that dendritic cells (DCs) are the primary initiators of naive CD4+ T cell responses. Nanoparticles, including virus-like particles (VLPs), are attractive candidates as carriers for vaccines and drug delivery. Using RNA phage Qß-derived VLP (Qß-VLP) as a model antigen, we found that antigen-specific B cells were the dominant antigen-presenting cells that initiated naive CD4+ T cell activation. B cells were sufficient to induce T follicular helper cell development in the absence of DCs. Qß-specific B cells promoted CD4+ T cell proliferation and differentiation via cognate interactions and through Toll-like receptor signaling-mediated cytokine production. Antigen-specific B cells were also involved in initiating CD4+ T cell responses during immunization with inactivated influenza virus. These findings have implications for the rational design of nanoparticles as vaccine candidates, particularly for therapeutic vaccines that aim to break immune tolerance.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunização/métodos , Vacinas contra Influenza/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos Virais/química , Antígenos Virais/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nanopartículas/química , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Receptores Toll-Like/imunologia , Vacinas de Produtos Inativados/imunologia
2.
J Immunol ; 213(2): 135-147, 2024 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-38829130

RESUMO

FOXP3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3Kδ is required for normal Treg development and function. However, the impacts of dysregulated PI3Kδ signaling on Treg function remain incompletely understood. In this study, we used a conditional mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the Treg compartment. Activated mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation, as demonstrated by increased memory/effector CD4+ and CD8+ T cells with enhanced IFN-γ secretion, spontaneous germinal center responses, and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype, including increased PD-1 expression and reduced competitive fitness. Consistent with these findings, Treg-specific aPIK3CD mice mounted an elevated humoral response following immunization with a T cell-dependent Ag, which correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3Kδ activity is critical for Treg homeostasis and function, suggesting that PI3Kδ signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Homeostase , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Homeostase/imunologia , Transdução de Sinais/imunologia , Camundongos Endogâmicos C57BL , Centro Germinativo/imunologia , Mutação com Ganho de Função , Doenças da Imunodeficiência Primária
3.
Nat Immunol ; 14(2): 136-42, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23263554

RESUMO

Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4(+) T(H)1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii resulted in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type-specific factors regulating T(H)1 polarization during T. gondii infection identified the T cell-intrinsic TLR pathway as a major regulator of IFN-γ production in CD4(+) T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.


Assuntos
Infecções por Enterobacteriaceae/patologia , Enterobacteriaceae/crescimento & desenvolvimento , Celulas de Paneth/patologia , Transdução de Sinais/imunologia , Células Th1/patologia , Toxoplasma/crescimento & desenvolvimento , Toxoplasmose Animal/patologia , Animais , Linfócitos T CD4-Positivos , Morte Celular , Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita , Interações Hospedeiro-Patógeno , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Celulas de Paneth/microbiologia , Celulas de Paneth/parasitologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/microbiologia , Células Th1/parasitologia , Toxoplasma/imunologia , Toxoplasmose Animal/complicações , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/parasitologia , alfa-Defensinas/deficiência
4.
Eur J Immunol ; 53(10): e2350437, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37438976

RESUMO

Toll-like receptor 7 (TLR7) triggers antiviral immune responses through its capacity to recognize single-stranded RNA. TLR7 loss-of-function mutants are associated with life-threatening pneumonia in severe COVID-19 patients. Whereas TLR7-driven innate induction of type I IFN appears central to control SARS-CoV2 virus spreading during the first days of infection, the impact of TLR7-deficiency on adaptive B-cell immunity is less clear. In the present study, we examined the role of TLR7 in the adaptive B cells response to various pathogen-like antigens (PLAs). We used inactivated SARS-CoV2 and a PLA-based COVID-19 vaccine candidate designed to mimic SARS-CoV2 with encapsulated bacterial ssRNA as TLR7 ligands and conjugated with the RBD of the SARS-CoV2 Spike protein. Upon repeated immunization with inactivated SARS-CoV2 or PLA COVID-19 vaccine, we show that Tlr7-deficiency abolished the germinal center (GC)-dependent production of RBD-specific class-switched IgG2b and IgG2c, and neutralizing antibodies to SARS-CoV2. We also provide evidence for a non-redundant role for B-cell-intrinsic TLR7 in the promotion of RBD-specific IgG2b/IgG2c and memory B cells. Together, these data demonstrate that the GC reaction and class-switch recombination to the Myd88-dependent IgG2b/IgG2c in response to SARS-CoV2 or PLAs is strictly dependent on cell-intrinsic activation of TLR7 in B cells.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , Anticorpos Neutralizantes/metabolismo , Receptor 7 Toll-Like , RNA Viral , Imunoglobulina G , Poliésteres , Anticorpos Antivirais
5.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33875594

RESUMO

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.


Assuntos
Imunogenicidade da Vacina/imunologia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animais , Anticorpos/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Imunidade Humoral/imunologia , Imunogenicidade da Vacina/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Células T Auxiliares Foliculares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação/métodos
6.
Immunol Rev ; 296(1): 24-35, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32304104

RESUMO

B cells have been known for their ability to present antigens to T cells for almost 40 years. However, the precise roles of B cell antigen presentation in various immune responses are not completely understood. The term "professional" antigen-presenting cells (APCs) was proposed to distinguish APCs that are required for initiating the immune responses from those use antigen presentation to enhance their own effector functions. Unlike dendritic cells, which are defined as professional APCs for their well-established functions in activating naive T cells, B cells have been shown in the past to mostly present antigens to activated CD4+ T cells mainly to seek help from T helper cells. However, recent evidence suggested that B cells can act as professional APCs under infectious conditions or conditions mimicking viral infections. B cell antigen receptors (BCRs) and the innate receptor Toll-like receptors are activated synergistically in response to pathogens or virus-like particles, under which conditions B cells are not only potent but also the predominant APCs to turn naive CD4+ T cells into T follicular helper cells. The discovery of B cells as professional APCs to initiate CD4+ T cell response provides a new insight for both autoimmune diseases and vaccine development.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoimunidade , Comunicação Celular/imunologia , Suscetibilidade a Doenças , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
Nat Immunol ; 12(12): 1184-93, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22019834

RESUMO

Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.


Assuntos
Colite/imunologia , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Espondilite Anquilosante/imunologia , Ubiquitina-Proteína Ligases/genética , Animais , Colite/patologia , Colite/prevenção & controle , Doença de Crohn/genética , Cisteína Endopeptidases , Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/metabolismo , Predisposição Genética para Doença , Homeostase/imunologia , Humanos , Doenças Linfáticas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Esplenomegalia/genética , Espondilite Anquilosante/patologia , Espondilite Anquilosante/prevenção & controle , Linfócitos T/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitina-Proteína Ligases/metabolismo
8.
J Immunol ; 207(9): 2217-2222, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34588220

RESUMO

Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/metabolismo , Autoimunidade , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Receptor Cross-Talk
9.
J Immunol ; 204(10): 2641-2650, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32253245

RESUMO

Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag-driven GC and Tfh responses in B6.Sle1b mice. By generating B cell-specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell-intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727-mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Fator de Transcrição STAT1/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/sangue , Autoantígenos/imunologia , Autoimunidade , Linfócitos B/transplante , Humanos , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fosforilação , Domínios Proteicos/genética , Fator de Transcrição STAT1/genética , Serina/genética , Ativação Transcricional , Quimeras de Transplante
10.
Proc Natl Acad Sci U S A ; 116(10): 4471-4480, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30770454

RESUMO

T cell antigen receptor (TCR) signaling is essential for the differentiation and maintenance of effector regulatory T (Treg) cells. However, the contribution of individual TCR-dependent genes in Treg cells to the maintenance of immunotolerance remains largely unknown. Here we demonstrate that Treg cells lacking E protein undergo further differentiation into effector cells that exhibit high expression of effector Treg signature genes, including IRF4, ICOS, CD103, KLRG-1, and RORγt. E protein-deficient Treg cells displayed increased stability and enhanced suppressive capacity. Transcriptome and ChIP-seq analyses revealed that E protein directly regulates a large proportion of the genes that are specific to effector Treg cell activation, and importantly, most of the up-regulated genes in E protein-deficient Treg cells are also TCR dependent; this indicates that E proteins comprise a critical gene regulatory network that links TCR signaling to the control of effector Treg cell differentiation and function.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Animais , Redes Reguladoras de Genes , Homeostase , Camundongos , Linfócitos T Reguladores/citologia
11.
Immunity ; 36(2): 228-38, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22306056

RESUMO

The Toll-like receptor adaptor protein MyD88 is essential for the regulation of intestinal homeostasis in mammals. In this study, we determined that Myd88-deficient mice are susceptible to colonic damage that is induced by dextran sulfate sodium (DSS) administration resulting from uncontrolled dissemination of intestinal commensal bacteria. The DSS-induced mortality of Myd88-deficient mice was completely prevented by antibiotic treatment to deplete commensal bacteria. By using cell type-specific Myd88-deficient mice, we established that B cell-intrinsic MyD88 signaling plays a central role in the resistance to DSS-induced colonic damage via the production of IgM and complement-mediated control of intestinal bacteria. Our results indicate that the lack of intact MyD88 signaling in B cells, coupled with impaired epithelial integrity, enables commensal bacteria to function as highly pathogenic organisms, causing rapid host death.


Assuntos
Linfócitos B/imunologia , Colo/imunologia , Colo/microbiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , Antibacterianos/farmacologia , Linfócitos B/metabolismo , Colo/efeitos dos fármacos , Colo/lesões , Proteínas do Sistema Complemento/metabolismo , Sulfato de Dextrana/toxicidade , Interações Hospedeiro-Patógeno/imunologia , Imunoglobulina A/metabolismo , Imunoglobulina M/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais
12.
J Immunol ; 203(11): 2817-2826, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31636237

RESUMO

Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of advanced age, during humoral autoimmunity and following viral infection, the functional properties of this cellular subset remain incompletely defined. In the current study, we demonstrate that ABCs fulfill the criteria for memory B cells (MBCs), based on evidence of Ag-dependent expansion and persistence in a state poised for rapid differentiation into Ab-secreting plasma cells during secondary responses. First, we show that a majority of ABCs are not actively cycling but exhibit an extensive replication history consistent with prior Ag engagement. Second, despite unswitched surface IgM expression, ABCs show evidence of activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Third, BCRs cloned from sorted ABCs exhibit broad autoreactivity and polyreactivity. Although the overall level of ABC self-reactivity was not increased relative to naive B cells, ABCs lacked features of functional anergy characteristic of autoreactive B cells. Fourth, ABCs express MBC surface markers consistent with being poised for rapid plasma cell differentiation during recall responses. Finally, in a murine model of viral infection, adoptively transferred CD11c+ B cells rapidly differentiated into class-switched Ab-secreting cells upon Ag rechallenge. In summary, we phenotypically and functionally characterize ABCs as IgM-expressing MBCs, findings that together implicate ABCs in the pathogenesis of systemic autoimmunity.


Assuntos
Envelhecimento/imunologia , Linfócitos B/imunologia , Antígeno CD11c/imunologia , Animais , Memória Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Immunity ; 34(3): 375-84, 2011 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-21353603

RESUMO

The contribution of Toll-like receptor (TLR) signaling to T cell-dependent (TD) antibody responses was assessed by using mice lacking the TLR signaling adaptor MyD88 in individual cell types. When a soluble TLR9 ligand was used as adjuvant for a protein antigen, MyD88 was required in dendritic cells but not in B cells to enhance the TD antibody response, regardless of the inherent immunogenicity of the antigen. In contrast, a TLR9 ligand contained within a virus-like particle substantially augmented the TD germinal center IgG antibody response, and this augmentation required B cell MyD88. The ability of B cells to discriminate between antigens based on the physical form of a TLR ligand probably reflects an adaptation to facilitate strong antiviral antibody responses.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Transdução de Sinais , Receptor Toll-Like 9/imunologia , Animais , Anticorpos Antivirais/sangue , Células Dendríticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Orthomyxoviridae/imunologia
14.
J Immunol ; 200(3): 937-948, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29282308

RESUMO

Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qß-derived virus-like particle (Qß-VLP) contains TLR ligands, which can enhance Qß-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qß-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response. Consistently, B cell-intrinsic MyD88 signaling significantly enhanced the initial proliferation of Ag-specific B cells, which was accompanied with a dramatic increase of plasma cell generation and induction of Bcl-6+ GC B cell precursors. In addition, B cell-intrinsic MyD88 signaling promoted strong T-bet expression independent of IFN-γ and led to the preferential isotype switching to IgG2a/c. Thus, by promoting the initial Ag-specific B cell proliferation and differentiation, B cell-intrinsic MyD88 signaling enhanced both T-independent and T-dependent Ab responses elicited by Qß-VLP. This finding will provide additional insight into the role of TLR signaling in antiviral immunity, autoimmune diseases, and vaccine design.


Assuntos
Allolevivirus/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Receptores Toll-Like/imunologia , Animais , Anticorpos Antivirais/imunologia , Diferenciação Celular/imunologia , Proliferação de Células/fisiologia , Feminino , Switching de Imunoglobulina/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais/imunologia , Proteínas com Domínio T/biossíntese , Proteínas Estruturais Virais/imunologia
15.
J Infect Dis ; 219(4): 648-659, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30312422

RESUMO

Background: Infection with the gram-negative bacillus Burkholderia pseudomallei (melioidosis) is an important cause of pneumosepsis in Southeast Asia and has a mortality of up to 40%. We aimed to assess the role of platelets in the host response against B. pseudomallei infection. Methods: Association between platelet counts and mortality was determined in 1160 patients with culture-proven melioidosis. Mice treated with (low- or high-dose) platelet-depleting antibody were inoculated intranasally with B. pseudomallei and killed. Additional studies using functional glycoprotein Ibα-deficient mice were conducted. Results: Thrombocytopenia was present in 31% of patients at admission and predicted mortality in melioidosis patients even after adjustment for confounders. In our murine-melioidosis model, platelet counts decreased, and mice treated with a platelet-depleting antibody showed enhanced mortality and higher bacterial loads compared to mice with normal platelet counts. Low platelet counts had a modest impact on early-pulmonary neutrophil influx. Reminiscent of their role in hemostasis, platelet depletion impaired vascular integrity, resulting in early lung bleeding. Glycoprotein Ibα-deficient mice had reduced platelet counts during B. pseudomallei infection together with an impaired local host defense in the lung. Conclusions: Thrombocytopenia predicts mortality in melioidosis patients and, during experimental melioidosis, platelets play a protective role in both innate immunity and vascular integrity.


Assuntos
Burkholderia pseudomallei/imunologia , Melioidose/complicações , Melioidose/patologia , Trombocitopenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sudeste Asiático , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Melioidose/imunologia , Melioidose/mortalidade , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Trombocitopenia/imunologia , Adulto Jovem
16.
J Immunol ; 198(10): 3846-3856, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28416599

RESUMO

Natural pathogens, such as viruses, often induce T-dependent and T-independent Ab responses. However, the activation and differentiation of Ag-specific B cells under these conditions had not been examined in detail. In this study, we used bacterial phage Qß-derived virus-like particles (Qß-VLPs) as an immunogen to examine the T-independent and T-dependent phases of the response in mice. Using Qß-specific cell labeling and enrichment methods developed in this study, we were able to characterize the rare Ag-specific B cells in detail. Surprisingly, we found that Qß-VLPs could induce Bcl-6 expression in pregerminal center B cells independently of T cell help. In addition, Qß-VLP-induced T-independent responses could lead to isotype-switched and somatically mutated memory B cells. Finally, in contrast to what has been reported with several other Ags, long-lived IgG+ memory cells were induced by Qß-VLPs, with IgM+ memory B cells being produced but only evident for a limited time, suggesting that different types of immunogens may preferentially generate or maintain IgM+ versus IgG+ memory B cells.


Assuntos
Linfócitos B/imunologia , Memória Imunológica , Linfócitos T/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Antivirais/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Coloração e Rotulagem , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem
17.
J Virol ; 91(22)2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28835502

RESUMO

Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8+ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8+ T cell response was elicited, major histocompatibility complex class I-restricted CD8+ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8+ T cells was developed, and virus-specific memory CD8+ T cells were generated in these mice. The CD8+ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8+ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection.IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8+ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8+ T cells in vivo, which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8+ T cell responses were generated and that CD8+ T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Imunidade Celular , Infecção por Zika virus/imunologia , Zika virus/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/patologia , Chlorocebus aethiops , Cricetinae , Camundongos , Células Vero , Infecção por Zika virus/patologia
18.
Am J Respir Cell Mol Biol ; 56(5): 648-656, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28187270

RESUMO

Klebsiella pneumoniae is a common cause of pneumonia. Previous studies have documented an important role for Toll-like receptors (TLRs) expressed by myeloid cells in the recognition of K. pneumoniae and the initiation of a protective immune response. Lung epithelial cells also express TLRs and can participate in innate immune defense. The aim of this study was to examine the role of the common TLR adaptor protein myeloid-differentiation factor (MyD) 88 in lung epithelium during host defense against K. pneumoniae-induced pneumonia. To this end, we first crossed mice expressing cre recombinase under the control of the surfactant protein C (SftpCcre) or the club cell 10 kD (CC10cre) promoter with reporter mice to show that SftpCcre mice mainly express cre in type II alveolar cells, whereas CC10cre mice express cre almost exclusively in bronchiolar epithelial cells. We then generated mice with cell-targeted deletion of MyD88 in type II alveolar (SftpCcre-MyD88-lox) and bronchiolar epithelial (CC10cre-MyD88-lox) cells, and infected them with K. pneumoniae via the airways. Bacterial growth and dissemination were not affected by the loss of MyD88 in SftpCcre-MyD88-lox or CC10cre-MyD88-lox mice compared with control littermates. Furthermore, inflammatory responses induced by K. pneumoniae in the lung were not dependent on MyD88 expression in type II alveolar or bronchiolar epithelial cells. These results indicate that MyD88 expression in two distinct lung epithelial cell types does not contribute to host defense during pneumonia caused by a common human gram-negative pathogen.


Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Infecções por Klebsiella/metabolismo , Klebsiella pneumoniae/fisiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Pneumonia Bacteriana/metabolismo , Animais , Bronquíolos/patologia , Células Epiteliais/patologia , Inflamação/patologia , Integrases/metabolismo , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/patologia , Camundongos , Viabilidade Microbiana , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Proteína C Associada a Surfactante Pulmonar/metabolismo , Uteroglobina/metabolismo
19.
Immunity ; 29(2): 272-82, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18656388

RESUMO

Toll-like receptors (TLRs) play prominent roles in initiating immune responses to infection, but their roles in particular cell types in vivo are not established. Here we report the generation of mice selectively lacking the crucial TLR-signaling adaptor MyD88 in dendritic cells (DCs). In these mice, the early production of inflammatory cytokines, especially IL-12, was substantially reduced after TLR stimulation. Whereas the innate interferon-gamma response of natural killer cells and of natural killer T cells and the Th1 polarization of antigen-specific CD4(+) T cells were severely compromised after treatment with a soluble TLR9 ligand, they were largely intact after administration of an aggregated TLR9 ligand. These results demonstrate that the physical form of a TLR ligand affects which cells can respond to it and that DCs and other innate immune cells can respond via TLRs and collaborate in promoting Th1 adaptive immune responses to an aggregated stimulus.


Assuntos
Células Dendríticas/imunologia , Imunidade Inata , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Imunidade Ativa , Switching de Imunoglobulina/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Oligodesoxirribonucleotídeos/farmacologia , Compostos de Amônio Quaternário/farmacologia , Recombinação Genética/genética , Recombinação Genética/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Receptores Toll-Like/imunologia
20.
Am J Physiol Lung Cell Mol Physiol ; 311(2): L219-28, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27288486

RESUMO

Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells.


Assuntos
Células Epiteliais Alveolares/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Pneumonia Bacteriana/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/imunologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/microbiologia , Animais , Flagelina/imunologia , Imunidade Inata , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Infiltração de Neutrófilos , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Transdução de Sinais , Receptor 5 Toll-Like/metabolismo
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