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1.
Nat Immunol ; 24(7): 1149-1160, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37202489

RESUMO

B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC-immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity.


Assuntos
Linfócitos B , Células Estromais , Camundongos , Humanos , Animais , Imunidade Humoral , Células Dendríticas Foliculares , Homeostase
2.
Nat Immunol ; 22(4): 510-519, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33707780

RESUMO

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.


Assuntos
Linhagem da Célula , Fibroblastos/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Comunicação Celular , Células Cultivadas , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Microbioma Gastrointestinal , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Interações Hospedeiro-Patógeno , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/virologia , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vírus da Hepatite Murina/imunologia , Vírus da Hepatite Murina/patogenicidade , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/virologia , Fenótipo , Análise de Célula Única , Transcriptoma
3.
Nat Immunol ; 21(6): 649-659, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424359

RESUMO

Efficient generation of germinal center (GC) responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells (BRCs). How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle. Here we used genetic targeting of Cxcl13-expressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCL12-dependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells. Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction.


Assuntos
Escuridão , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunomodulação/efeitos da radiação , Luz , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Comunicação Celular , Quimiocina CXCL12/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Nat Immunol ; 17(12): 1388-1396, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27798617

RESUMO

Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.


Assuntos
Citrobacter rodentium/imunologia , Infecções por Coronavirus/imunologia , Infecções por Enterobacteriaceae/imunologia , Fibroblastos/imunologia , Interleucina-15/metabolismo , Linfócitos/imunologia , Vírus da Hepatite Murina/imunologia , Animais , Células Cultivadas , Imunidade Inata , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Nódulos Linfáticos Agregados/patologia , Células Th1/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo
5.
Circ Res ; 134(12): 1703-1717, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38843287

RESUMO

Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell-cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation.


Assuntos
Fibroblastos , Homeostase , Miocárdio , Humanos , Animais , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/imunologia , Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Inflamação/imunologia , Miocardite/imunologia , Miocardite/patologia , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Comunicação Celular
6.
Immunity ; 44(3): 622-633, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26921107

RESUMO

Stromal cells generate a complex cellular scaffold that provides specialized microenvironments for lymphocyte activation in secondary lymphoid organs. Here, we assessed whether local activation of stromal cells in the central nervous system (CNS) is mandatory to transfer immune recognition from secondary lymphoid organs into the infected tissue. We report that neurotropic virus infection in mice triggered the establishment of such stromal cell niches in the CNS. CNS stromal cell activation was dominated by a rapid and vigorous production of CC-motif chemokine receptor (CCR) 7 ligands CCL19 and CCL21 by vascular endothelial cells and adjacent fibroblastic reticular cell (FRC)-like cells in the perivascular space. Moreover, CCR7 ligands produced by CNS stromal cells were crucial to support recruitment and local re-activation of antiviral CD8(+) T cells and to protect the host from lethal neuroinflammatory disease, indicating that CNS stromal cells generate confined microenvironments that control protective T cell immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Sistema Nervoso Central/imunologia , Endotélio Vascular/imunologia , Vírus da Hepatite A/imunologia , Hepatite A/imunologia , Inflamação Neurogênica/parasitologia , Receptores CCR7/metabolismo , Células Estromais/imunologia , Animais , Movimento Celular , Microambiente Celular , Sistema Nervoso Central/virologia , Quimiocina CCL19/metabolismo , Quimiocina CCL21/metabolismo , Endotélio Vascular/virologia , Hepatite A/complicações , Imunidade Celular , Imunomodulação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Inflamação Neurogênica/etiologia , Receptores CCR7/genética , Células Estromais/virologia , Tropismo Viral
7.
Immunol Rev ; 289(1): 31-41, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977192

RESUMO

Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune-interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat-associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses.


Assuntos
Tecido Adiposo/imunologia , Fibroblastos/imunologia , Tecido Linfoide/imunologia , Células Estromais/imunologia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa , Animais , Homeostase , Humanos , Imunidade Inata , Imunomodulação , Ativação Linfocitária
8.
Immunity ; 38(5): 1013-24, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23623380

RESUMO

The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-ß receptor (LTßR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTßR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTßR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.


Assuntos
Infecções por Coronavirus/imunologia , Linfonodos/citologia , Linfonodos/metabolismo , Miofibroblastos/fisiologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/imunologia , Interleucina-7/biossíntese , Linfonodos/imunologia , Receptor beta de Linfotoxina/metabolismo , Linfotoxina-beta/biossíntese , Linfotoxina-beta/metabolismo , Glicoproteínas de Membrana/biossíntese , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vírus da Hepatite Murina/imunologia , Miofibroblastos/citologia , Transdução de Sinais
9.
Basic Res Cardiol ; 115(1): 6, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863205

RESUMO

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/fisiologia , Miocardite/imunologia , Miocárdio/patologia , Animais , Fibrose/imunologia , Humanos , Camundongos , Miocárdio/imunologia
10.
PLoS Pathog ; 13(2): e1006195, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28158275

RESUMO

Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I). This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.


Assuntos
Coronaviridae/enzimologia , Infecções por Coronavirus/imunologia , Endonucleases/imunologia , Evasão da Resposta Imune/fisiologia , Proteínas Virais/imunologia , Animais , Coronaviridae/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real
11.
J Immunol ; 192(11): 5192-200, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24778443

RESUMO

Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Centro Germinativo/imunologia , Imunoglobulina M/imunologia , Memória Imunológica , Interferon gama/imunologia , Salmonella typhi/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Feminino , Centro Germinativo/patologia , Humanos , Interferon gama/genética , Masculino , Camundongos , Camundongos Knockout , Vacinas contra Salmonella/genética , Vacinas contra Salmonella/imunologia , Febre Tifoide/genética , Febre Tifoide/imunologia , Febre Tifoide/patologia , Febre Tifoide/prevenção & controle
12.
PLoS Pathog ; 9(10): e1003663, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24098121

RESUMO

Viruses that generate capped RNA lacking 2'O methylation on the first ribose are severely affected by the antiviral activity of Type I interferons. We used proteome-wide affinity purification coupled to mass spectrometry to identify human and mouse proteins specifically binding to capped RNA with different methylation states. This analysis, complemented with functional validation experiments, revealed that IFIT1 is the sole interferon-induced protein displaying higher affinity for unmethylated than for methylated capped RNA. IFIT1 tethers a species-specific protein complex consisting of other IFITs to RNA. Pulsed stable isotope labelling with amino acids in cell culture coupled to mass spectrometry as well as in vitro competition assays indicate that IFIT1 sequesters 2'O-unmethylated capped RNA and thereby impairs binding of eukaryotic translation initiation factors to 2'O-unmethylated RNA template, which results in inhibition of translation. The specificity of IFIT1 for 2'O-unmethylated RNA serves as potent antiviral mechanism against viruses lacking 2'O-methyltransferase activity and at the same time allows unperturbed progression of the antiviral program in infected cells.


Assuntos
Proteínas de Transporte/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Iniciação Traducional da Cadeia Peptídica , Capuzes de RNA/metabolismo , Viroses/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/genética , Chlorocebus aethiops , Fatores de Iniciação em Eucariotos/genética , Células HeLa , Humanos , Metilação , Camundongos , Camundongos Knockout , Capuzes de RNA/genética , Processamento Pós-Transcricional do RNA/genética , Proteínas de Ligação a RNA , Células Vero , Viroses/genética
13.
Proc Natl Acad Sci U S A ; 109(4): 1233-8, 2012 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-22232667

RESUMO

Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell-deficient mice failed to contain MHV CNS infection and developed progressive demyelinating disease, germline IgM produced in activation-induced cytidine deaminase-deficient mice (aicda(-/-)) provided long-term protection against the chronic multiple sclerosis-like disease. Furthermore, we found that appropriate B-cell activation within the CNS-draining lymph node and subsequent CXCR3-mediated migration of antiviral IgM-secreting cells to the infected CNS was dependent on CD40-mediated interaction of B cells with T helper cells. These data indicate that the CD40-mediated collaboration of T and B cells is critical to secure neuroprotective IgM responses during viral CNS infection.


Assuntos
Antígenos CD40/imunologia , Sistema Nervoso Central/virologia , Doenças Desmielinizantes/virologia , Imunoglobulina M/imunologia , Vírus da Hepatite Murina/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Análise de Variância , Animais , Linfócitos B/imunologia , Sistema Nervoso Central/imunologia , Citidina Desaminase/deficiência , Doenças Desmielinizantes/imunologia , ELISPOT , Citometria de Fluxo , Imunofluorescência , Imunoglobulina M/genética , Camundongos , Camundongos Knockout
14.
Nat Cardiovasc Res ; 3(3): 301-316, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-39196111

RESUMO

Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.


Assuntos
Doenças Autoimunes , Proteína Morfogenética Óssea 4 , Modelos Animais de Doenças , Fibrose , Miocardite , Miocardite/metabolismo , Miocardite/patologia , Miocardite/imunologia , Animais , Fibrose/patologia , Fibrose/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 4/genética , Humanos , Doenças Autoimunes/patologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/imunologia , Masculino , Transdução de Sinais , Camundongos , Microambiente Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Feminino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/imunologia
15.
Immunology ; 139(4): 459-71, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23432484

RESUMO

Salmonella enterica serovar Typhi (S. Typhi) is the causal agent of typhoid fever, a disease that primarily affects developing countries. Various antigens from this bacterium have been reported to be targets of the immune response. Recently, the S. Typhi genome has been shown to encode two porins--OmpS1 and OmpS2--which are expressed at low levels under in vitro culture conditions. In this study, we demonstrate that immunizing mice with either OmpS1 or OmpS2 induced production of specific, long-term antibody titres and conferred protection against S. Typhi challenge; in particular, OmpS1 was more immunogenic and conferred greater protective effects than OmpS2. We also found that OmpS1 is a Toll-like receptor 4 (TLR4) agonist, whereas OmpS2 is a TLR2 and TLR4 agonist. Both porins induced the production of tumour necrosis factor and interleukin-6, and OmpS2 was also able to induce interleukin-10 production. Furthermore, OmpS1 induced the over-expression of MHC II molecules in dendritic cells and OmpS2 induced the over-expression of CD40 molecules in macrophages and dendritic cells. Co-immunization of OmpS1 or OmpS2 with ovalbumin (OVA) increased anti-OVA antibody titres, the duration and isotype diversity of the OVA-specific antibody response, and the proliferation of T lymphocytes. These porins also had adjuvant effects on the antibody response when co-immunized with either the Vi capsular antigen from S. Typhi or inactivated 2009 pandemic influenza A(H1N1) virus [A(H1N1)pdm09]. Taken together, the data indicate that OmpS1 and OmpS2, despite being expressed at low levels under in vitro culture conditions, are potent protective immunogens with intrinsic adjuvant properties.


Assuntos
Adjuvantes Imunológicos , Anticorpos Antibacterianos/sangue , Proteínas da Membrana Bacteriana Externa/imunologia , Porinas/imunologia , Vacinas contra Salmonella/imunologia , Salmonella typhi/imunologia , Febre Tifoide/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/genética , Animais , Proteínas da Membrana Bacteriana Externa/administração & dosagem , Proteínas da Membrana Bacteriana Externa/genética , Células Dendríticas/imunologia , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunização , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/imunologia , Polissacarídeos Bacterianos/imunologia , Porinas/administração & dosagem , Porinas/genética , Vacinas contra Salmonella/administração & dosagem , Vacinas contra Salmonella/genética , Salmonella typhi/genética , Linfócitos T/imunologia , Fatores de Tempo , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/metabolismo , Transfecção , Fator de Necrose Tumoral alfa/metabolismo , Febre Tifoide/sangue , Febre Tifoide/imunologia , Febre Tifoide/microbiologia
16.
Eur J Immunol ; 41(6): 1606-18, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21469112

RESUMO

Clearance of disseminated Salmonella infection requires bacterial-specific Th1 cells and IFN-γ production, and Th1-promoting vaccines are likely to help control these infections. Consequently, vaccine design has focused on developing Th1-polarizing adjuvants or Ag that naturally induce Th1 responses. In this study, we show that, in mice, immunization with soluble, recombinant FliC protein flagellin (sFliC) induces Th2 responses as evidenced by Ag-specific GATA-3, IL-4 mRNA, and protein induction in CD62L(lo) CD4(+) T cells without associated IFN-γ production. Despite these Th2 features, sFliC immunization can enhance the development of protective Th1 immunity during subsequent Salmonella infection in an Ab-independent, T-cell-dependent manner. Salmonella infection in sFliC-immunized mice resulted in augmented Th1 responses, with greater bacterial clearance and increased numbers of IFN-γ-producing CD4(+) T cells, despite the early induction of Th2 features to sFliC. The augmented Th1 immunity after sFliC immunization was regulated by T-bet although T-bet is dispensable for primary responses to sFliC. These findings show that there can be flexibility in T-cell responses to some subunit vaccines. These vaccines may induce Th2-type immunity during primary immunization yet promote Th1-dependent responses during later infection. This suggests that designing Th1-inducing subunit vaccines may not always be necessary since this can occur naturally during subsequent infection.


Assuntos
Vacinas Bacterianas , Flagelina/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Carga Bacteriana , Células Cultivadas , Regulação da Expressão Gênica , Imunização , Interferon gama/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Salmonella/microbiologia , Salmonella typhimurium/crescimento & desenvolvimento , Salmonella typhimurium/patogenicidade , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Células Th1/imunologia , Células Th1/microbiologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/microbiologia , Células Th2/patologia
17.
Proc Natl Acad Sci U S A ; 106(24): 9803-8, 2009 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-19487686

RESUMO

Invasive nontyphoidal Salmonella (NTS), including Salmonella typhimurium (STm), are major yet poorly-recognized killers of infants in sub-Saharan Africa. Death in these children is usually associated with bacteremia, commonly in the absence of gastrointestinal symptoms. Evidence from humans and animal studies suggest that severe infection and bacteremia occur when specific Ab is lacking. Understanding how Ab responses to Salmonella are regulated will help develop vaccines against these devastating infections. STm induces atypical Ab responses characterized by prominent, accelerated, extrafollicular T-independent (TI) Ab against a range of surface antigens. These responses develop without concomitant germinal centers, which only appear as infection resolves. Here, we show STm rapidly induces a population of TI B220(+)CD5(-) B1b cells during infection and TI Ab from B1b cells targets the outer membrane protein (Omp) porins OmpC, OmpD and OmpF but not flagellin. When porins are used as immunogens they can ablate bacteremia and provide equivalent protection against STm as killed bacterial vaccine and this is wholly B cell-dependent. Furthermore Ab from porin-immunized chimeras, that have B1b cells, is sufficient to impair infection. Infecting with porin-deficient bacteria identifies OmpD, a protein absent from Salmonella Typhi, as a key target of Ab in these infections. This work broadens the recognized repertoire of TI protein antigens and highlights the importance of Ab from different B cell subsets in controlling STm infection. OmpD is a strong candidate vaccine target and may, in part, explain the lack of cross-protection between Salmonella Typhi and STm infections.


Assuntos
Anticorpos Antibacterianos/biossíntese , Porinas/imunologia , Salmonella/metabolismo , Animais , Linfócitos B/citologia , Sequência de Bases , Western Blotting , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Camundongos , Cavidade Peritoneal/citologia , Salmonella/imunologia
18.
Nat Commun ; 13(1): 2027, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440118

RESUMO

Innate lymphoid cells (ILCs) govern immune cell homeostasis in the intestine and protect the host against microbial pathogens. Various cell-intrinsic pathways have been identified that determine ILC development and differentiation. However, the cellular components that regulate ILC sustenance and function in the intestinal lamina propria are less known. Using single-cell transcriptomic analysis of lamina propria fibroblasts, we identify fibroblastic reticular cells (FRCs) that underpin cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Genetic ablation of lymphotoxin-ß receptor expression in Ccl19-expressing FRCs blocks the maturation of CPs into mature ILFs. Interactome analysis shows the major niche factors and processes underlying FRC-ILC crosstalk. In vivo validation confirms that a sustained lymphotoxin-driven feedforward loop of FRC activation including IL-7 generation is critical for the maintenance of functional ILC populations. In sum, our study indicates critical fibroblastic niches within the intestinal lamina propria that control ILC homeostasis and functionality and thereby secure protective gut immunity.


Assuntos
Imunidade Inata , Linfócitos , Fibroblastos , Homeostase , Intestinos
19.
Immunology ; 133(4): 469-81, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21631497

RESUMO

Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4(+) T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Lipopolissacarídeos/imunologia , Salmonella typhimurium/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Lipopolissacarídeos/química , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Salmonella typhimurium/química , Taxa de Sobrevida , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/imunologia
20.
Nat Commun ; 12(1): 4734, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354077

RESUMO

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.


Assuntos
Melanoma Experimental/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Reprogramação Celular/métodos , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Feminino , Vetores Genéticos , Interleucina-33/deficiência , Interleucina-33/genética , Interleucina-33/imunologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Vírus da Coriomeningite Linfocítica/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/imunologia
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