Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 171
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 184(19): 4848-4856, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34480864

RESUMO

Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.


Assuntos
SARS-CoV-2/fisiologia , Animais , Evolução Biológica , COVID-19/virologia , Humanos , Laboratórios , SARS-CoV-2/genética , Zoonoses/virologia
2.
Nat Immunol ; 14(5): 480-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23525089

RESUMO

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.


Assuntos
Alphainfluenzavirus/imunologia , Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Mitocôndrias/fisiologia , Mitofagia , Infecções por Orthomyxoviridae/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Caspase 1/metabolismo , Células Cultivadas , Imunidade Ativa/genética , Interleucina-18/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Transdução de Sinais/genética , Superóxidos/metabolismo , Fatores de Virulência/genética
3.
Nat Immunol ; 14(12): 1266-76, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24141387

RESUMO

Highly pathogenic avian influenza viruses pose a continuing global threat. Current vaccines will not protect against newly evolved pandemic viruses. The creation of 'universal' vaccines has been unsuccessful because the immunological mechanisms that promote heterosubtypic immunity are incompletely defined. We found here that rapamycin, an immunosuppressive drug that inhibits the kinase mTOR, promoted cross-strain protection against lethal infection with influenza virus of various subtypes when administered during immunization with influenza virus subtype H3N2. Rapamycin reduced the formation of germinal centers and inhibited class switching in B cells, which yielded a unique repertoire of antibodies that mediated heterosubtypic protection. Our data established a requirement for the mTORC1 complex in B cell class switching and demonstrated that rapamycin skewed the antibody response away from high-affinity variant epitopes and targeted more conserved elements of hemagglutinin. Our findings have implications for the design of a vaccine against influenza virus.


Assuntos
Imunidade Adaptativa/imunologia , Formação de Anticorpos/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Serina-Treonina Quinases TOR/imunologia , Animais , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular , Feminino , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Switching de Imunoglobulina/efeitos dos fármacos , Switching de Imunoglobulina/imunologia , Imunoglobulina M/imunologia , Imunossupressores/farmacologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Orthomyxoviridae/classificação , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Sirolimo/farmacologia , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
4.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34607957

RESUMO

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.


Assuntos
Anticorpos Antivirais/sangue , Povos Indígenas/estatística & dados numéricos , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Ativação Linfocitária/imunologia , Austrália , Linfócitos B/imunologia , Humanos , Imunoglobulina G/sangue , Memória Imunológica/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Contagem de Linfócitos , Vacinação em Massa , Risco , Células T Auxiliares Foliculares/imunologia , Linfócitos T/imunologia
5.
Proc Natl Acad Sci U S A ; 117(39): 24384-24391, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32913053

RESUMO

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that A2/S269+CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269+CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269+CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269+CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Antígeno HLA-A2/imunologia , Pneumonia Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , COVID-19 , Epitopos de Linfócito T , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Poliproteínas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas Virais/química , Proteínas Virais/imunologia
6.
Nat Immunol ; 11(10): 875-8, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20856214

RESUMO

The Nobel Prizes will be announced at the beginning of October. Is there a possibility that immunology might make the list?


Assuntos
Alergia e Imunologia/história , Prêmio Nobel , Pesquisa Biomédica/história , História do Século XX
7.
Proc Natl Acad Sci U S A ; 116(10): 4481-4488, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30787194

RESUMO

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8+ cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4+ T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4+ T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8+ T cell memory established in the presence or absence of a concurrent CD4+ T cell response. We demonstrate that CD4+ T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with "unhelped" memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more "exhausted T cell" transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4+ T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8+ T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A/imunologia , Animais , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação Oxidativa , Transcrição Gênica
8.
Nat Immunol ; 10(1): 14-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19088735

RESUMO

A systems biology approach provides correlates of successful vaccination, which allows a new method for measuring early vaccine efficiency and suggests hypotheses for the mechanisms that underlie immunogenicity.


Assuntos
Algoritmos , Perfilação da Expressão Gênica/métodos , Biologia de Sistemas/métodos , Vacinação , Vacina contra Febre Amarela/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Camundongos , Proteoma , Resultado do Tratamento , Febre Amarela/prevenção & controle , Vacina contra Febre Amarela/uso terapêutico
9.
Proc Natl Acad Sci U S A ; 113(16): 4440-5, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27036003

RESUMO

Memory CD8(+)T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M158and the hypervariable HLA-B*3501-NP418antigens. The TCRαßs for HLA-B*3501-NP418 (+)CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19(+)TCRαß was selected in HLA-A*0201(+)donors responding to M158 This public TCR cross-recognized naturally occurring M158variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19(+)TCR specificity for the WT and mutant M158peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201(+)individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M158 Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno HLA-A2 , Imunidade Celular , Vírus da Influenza A/imunologia , Influenza Humana , Receptores de Antígenos de Linfócitos T alfa-beta , Animais , Antígenos Virais/imunologia , Cães , Feminino , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Humanos , Memória Imunológica/genética , Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/imunologia , Células Madin Darby de Rim Canino , Masculino , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Vacinação , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/farmacologia
10.
Proc Natl Acad Sci U S A ; 113(5): 1333-8, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26787864

RESUMO

In advanced age, decreased CD8(+) cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8(+) T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8(+) T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8(+) T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8(+) T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8(+) T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL
11.
Proc Natl Acad Sci U S A ; 113(36): 10133-8, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27543331

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur.


Assuntos
Imunidade nas Mucosas , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Humana/imunologia , Interleucina-18/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Pneumonia Viral/imunologia , Células A549 , Comunicação Celular/imunologia , Técnicas de Cocultura , Expressão Gênica , Granzimas/genética , Granzimas/imunologia , Humanos , Imunidade Inata , Imunofenotipagem , Subtipo H7N9 do Vírus da Influenza A/imunologia , Influenza Humana/mortalidade , Influenza Humana/patologia , Influenza Humana/virologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-18/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Ativação Linfocitária , Monócitos/imunologia , Monócitos/virologia , Células T Invariantes Associadas à Mucosa/virologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Transdução de Sinais , Análise de Sobrevida
12.
Immunol Cell Biol ; 96(10): 1104-1119, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29972699

RESUMO

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T-cell priming events influence lasting memory, which is required for long-term protection. However, the early responding, IAV-specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV-specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+ CD43+ IAV-specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T-cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV-specific CD8+ T-cell population. Subsequently, IAV-specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T-cell response. Importantly, the CD25+ CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , Epitopos/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucossialina/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Infecções por Orthomyxoviridae/metabolismo , Fenótipo , Multimerização Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia
13.
Immunity ; 30(4): 566-75, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19362023

RESUMO

Virus-induced interlukin-1beta (IL-1beta) and IL-18 production in macrophages are mediated via caspase-1 pathway. Multiple microbial components, including viral RNA, are thought to trigger assembly of the cryopyrin inflammasome resulting in caspase-1 activation. Here, we demonstrated that Nlrp3(-/-) and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus. This enhanced morbidity correlated with decreased neutrophil and monocyte recruitment and reduced cytokine and chemokine production. Despite the effect on innate immunity, cryopyrin-deficiency was not associated with any obvious defect in virus control or on the later emergence of the adaptive response. Early epithelial necrosis was, however, more severe in the infected mutants, with extensive collagen deposition leading to later respiratory compromise. These findings reveal a function of the cryopyrin inflammasome in healing responses. Thus, cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.


Assuntos
Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Imunidade Inata , Vírus da Influenza A/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Proteínas de Transporte/genética , Caspase 1/genética , Células Cultivadas , Regulação da Expressão Gênica , Predisposição Genética para Doença , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR
14.
PLoS Pathog ; 11(2): e1004642, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25668410

RESUMO

The recent emergence of a novel H7N9 influenza A virus (IAV) causing severe human infections in China raises concerns about a possible pandemic. The lack of pre-existing neutralizing antibodies in the broader population highlights the potential protective role of IAV-specific CD8(+) cytotoxic T lymphocyte (CTL) memory specific for epitopes conserved between H7N9 and previously encountered IAVs. In the present study, the heterosubtypic immunity generated by prior H9N2 or H1N1 infections significantly, but variably, reduced morbidity and mortality, pulmonary virus load and time to clearance in mice challenged with the H7N9 virus. In all cases, the recall of established CTL memory was characterized by earlier, greater airway infiltration of effectors targeting the conserved or cross-reactive H7N9 IAV peptides; though, depending on the priming IAV, each case was accompanied by distinct CTL epitope immunodominance hierarchies for the prominent K(b)PB(1703, D(b)PA(224), and D(b)NP(366) epitopes. While the presence of conserved, variable, or cross-reactive epitopes between the priming H9N2 and H1N1 and the challenge H7N9 IAVs clearly influenced any change in the immunodominance hierarchy, the changing patterns were not tied solely to epitope conservation. Furthermore, the total size of the IAV-specific memory CTL pool after priming was a better predictor of favorable outcomes than the extent of epitope conservation or secondary CTL expansion. Modifying the size of the memory CTL pool significantly altered its subsequent protective efficacy on disease severity or virus clearance, confirming the important role of heterologous priming. These findings establish that both the protective efficacy of heterosubtypic immunity and CTL immunodominance hierarchies are reflective of the immunological history of the host, a finding that has implications for understanding human CTL responses and the rational design of CTL-mediated vaccines.


Assuntos
Epitopos de Linfócito T/imunologia , Imunidade Heteróloga/imunologia , Epitopos Imunodominantes/imunologia , Memória Imunológica/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
J Immunol ; 194(3): 898-910, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25535284

RESUMO

The characteristics of the TCR repertoire expressed by epitope-specific CD8(+) T cells can be an important determinant of the quality of immune protection against virus infection. Most studies of epitope-specific TCR repertoires focus solely on an analysis of TCR ß-chains, rather than the combined TCRαß heterodimers that confer specificity. Hence, the importance of complementary α- and ß-chain pairing in determining TCR specificity and T cell function is not well understood. Our earlier study of influenza-specific TCR repertoires in a C57BL/6J mouse model described a structural basis for preferred TCRαß pairing that determined exquisite specificity for the D(b)PA224 epitope from influenza A virus. We have now extended this analysis using retrogenic mice engineered to express single TCR α- or ß-chains specific for the D(b)NP366 or D(b)PA224 epitopes derived from influenza A virus. We found that particular TCRαß combinations were selected for recognition of these epitopes following infection, indicating that pairing of certain α- and ß-chain sequences is key for determining TCR specificity. Furthermore, we demonstrated that some TCRαß heterodimers were preferentially expanded from the naive repertoire in response to virus infection, suggesting that appropriate αß pairing confers optimal T cell responsiveness to Ag.


Assuntos
Epitopos de Linfócito T/imunologia , Variação Genética , Antígenos de Histocompatibilidade Classe I/imunologia , Vírus da Influenza A/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Sequência de Aminoácidos , Animais , Linhagem Celular , Sequência Conservada , Feminino , Imunidade Celular/genética , Imunidade Celular/imunologia , Camundongos , Camundongos Transgênicos , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
16.
Proc Natl Acad Sci U S A ; 111(4): 1485-90, 2014 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-24474775

RESUMO

The recall of memory CD8(+) cytotoxic T lymphocytes (CTLs), elicited by prior virus infection or vaccination, is critical for immune protection. The extent to which this arises as a consequence of stochastic clonal expansion vs. active selection of particular clones remains unclear. Using a parallel adoptive transfer protocol in combination with single cell analysis to define the complementarity determining region (CDR) 3α and CDR3ß regions of individual T-cell receptor (TCR) heterodimers, we characterized the antigen-driven recall of the same memory CTL population in three individual recipients. This high-resolution analysis showed reproducible enrichment (or diminution) of particular TCR clonotypes across all challenged animals. These changes in clonal composition were TCRα- and ß chain-dependent and were directly related to the avidity of the TCR for the virus-derived peptide (p) + major histocompatibility complex class I molecule. Despite this shift in clonotype representation indicative of differential selection, there was no evidence of overall repertoire narrowing, suggesting a strategy to optimize CTL responses while safeguarding TCR diversity.


Assuntos
Afinidade de Anticorpos , Linfócitos T CD8-Positivos/imunologia , Infecções por Orthomyxoviridae/imunologia , Sequência de Aminoácidos , Animais , Células Clonais , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Infecções por Orthomyxoviridae/complicações , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Reprodutibilidade dos Testes
17.
Proc Natl Acad Sci U S A ; 111(3): 1049-54, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24395804

RESUMO

The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus-specific CD8(+) T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16-57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Influenza Humana/etnologia , Influenza Humana/imunologia , Austrália , Reações Cruzadas/imunologia , Cristalografia por Raios X , Epitopos de Linfócito T/imunologia , Etnicidade , Antígenos HLA/imunologia , Antígenos HLA-A/imunologia , Humanos , Memória Imunológica , Vacinas contra Influenza/imunologia , Leucócitos Mononucleares/citologia , Funções Verossimilhança , Mutação , Peptídeos/imunologia
18.
Proc Natl Acad Sci U S A ; 111(2): 769-74, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24367104

RESUMO

A unique avian-origin A/H7N9 influenza virus has so far caused 134 cases with 44 deaths. Probing the host factors contributing to disease severity, we found that lower levels of plasma inflammatory cytokines on hospital admission correlated with faster recovery in 18 patients with A/H7N9 influenza virus, whereas high concentrations of (in particular) IL-6, IL-8, and macrophage inflammatory protein-1ß were predictive of a less favorable or fatal outcome. Analysis of bronchoalveolar lavage samples showed up to 1,000-fold greater cytokine/chemokine levels relative to plasma. Furthermore, patients with the rs12252-C/C IFN-induced transmembrane protein-3 (IFITM3) genotype had more rapid disease progression and were less likely to survive. Compared with patients with the rs12252-T/T or rs12252-T/C genotype of IFITM3, patients with the C/C genotype had a shorter time from disease onset to the time point when they sought medical aid (hospital admission or antiviral therapy) and a shorter interval to development of the acute respiratory distress syndrome stage (reflected by shorter intervals between clinical onset and methylprednisolone treatments and higher rates of mechanical ventilator use), as well as experiencing elevated/prolonged lung virus titers and cytokine production and higher mortality. The present analysis provides reported data on the H7N9 influenza-induced "cytokine storm" at the site of infection in humans and identifies the rs12252-C genotype that compromises IFITM3 function as a primary genetic correlate of severe H7N9 pneumonia. Together with rs12252 sequencing, early monitoring of plasma cytokines is thus of prognostic value for the treatment and management of severe influenza pneumonia.


Assuntos
Citocinas/imunologia , Surtos de Doenças/história , Subtipo H7N9 do Vírus da Influenza A , Influenza Humana/epidemiologia , Influenza Humana/genética , Influenza Humana/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sequência de Bases , China/epidemiologia , Citocinas/sangue , Primers do DNA/genética , Genótipo , História do Século XXI , Humanos , Pulmão/imunologia , Proteínas de Membrana/genética , Dados de Sequência Molecular , Prognóstico , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Estatísticas não Paramétricas
19.
Nat Rev Immunol ; 6(12): 883-94, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17110956

RESUMO

Antigen-specific T-cell responses induced by infection, transplantation, autoimmunity or hypersensitivity are characterized by cells expressing biased profiles of T-cell receptors (TCRs) that are selected from a diverse, naive repertoire. Here, we review the evidence for these TCR biases, focusing on crystallographic analysis of the structural constraints that determine the binding of a TCR to its ligand and the persistence of certain TCRs in an immune repertoire. We discuss the ways in which diversity in a selected TCR repertoire can contribute to protective immunity and the implications of this for vaccine design and immunotherapy.


Assuntos
Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Vírus/imunologia , Animais , Variação Genética , Humanos , Imunidade/genética , Camundongos , Conformação Proteica , Receptores de Antígenos de Linfócitos T/imunologia
20.
Immunol Cell Biol ; 94(8): 729-40, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27101922

RESUMO

CD4 T follicular helper cells (TFH) are critical in the generation of potent and long-lived B-cell responses after viral infection. However, the factors that dictate the generation and maintenance of these cells are not fully understood. Here we use adoptive transfer of OTII T-cell receptor transgenic CD4 T cells, followed by infection with recombinant influenza A virus (IAV), as a means of identifying and tracking virus-specific CD4(+) T-cell responses. We show that T-cell competition within the virus-specific CD4 T-cell pool induced by IAV infection limits the proliferation and differentiation of IAV-specific CD4(+) TFH responses. In particular, increased T-cell competition for antigen results in a diminished IAV-specific TFH CD4 T-cell responses, particularly germinal center TFH responses. Strikingly, competition in the form of preexisting cellular immunity generated by heterosubtypic IAV immunization limits de novo CD4 T-cell responses in secondary lymphoid tissue. Taken together, these data show a profound linkage between antigen availability and promotion of TFH CD4(+) T-cell responses in response to infection. These data suggest that competition within the CD4 T-cell pool limits TFH responses and may be an important regulatory mechanism for controlling immunity.


Assuntos
Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Diferenciação Celular , Divisão Celular , Proliferação de Células , Células Clonais , Centro Germinativo/citologia , Imunidade , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/sangue , Infecções por Orthomyxoviridae/patologia , Fenótipo , Especificidade da Espécie
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA