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1.
Cell ; 175(2): 387-399.e17, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30270043

RESUMO

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , Vacinas contra a AIDS/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adulto , Linfócitos B/imunologia , Linhagem Celular , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica/métodos , Anticorpos Anti-HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1/patogenicidade , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Masculino , Pessoa de Meia-Idade
2.
Nat Immunol ; 21(2): 199-209, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959979

RESUMO

A goal of HIV vaccine development is to elicit antibodies with neutralizing breadth. Broadly neutralizing antibodies (bNAbs) to HIV often have unusual sequences with long heavy-chain complementarity-determining region loops, high somatic mutation rates and polyreactivity. A subset of HIV-infected individuals develops such antibodies, but it is unclear whether this reflects systematic differences in their antibody repertoires or is a consequence of rare stochastic events involving individual clones. We sequenced antibody heavy-chain repertoires in a large cohort of HIV-infected individuals with bNAb responses or no neutralization breadth and uninfected controls, identifying consistent features of bNAb repertoires, encompassing thousands of B cell clones per individual, with correlated T cell phenotypes. These repertoire features were not observed during chronic cytomegalovirus infection in an independent cohort. Our data indicate that the development of numerous B cell lineages with antibody features associated with autoreactivity may be a key aspect in the development of HIV neutralizing antibody breadth.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/imunologia
3.
Nat Immunol ; 23(12): 1654-1656, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36443516

Assuntos
Vacinas
4.
EMBO Rep ; 22(8): e52447, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34142428

RESUMO

Cyclic GMP-AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus-like particles (VLPs) containing HIV-1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV-G). cGAMP loading of VLPs augments CD4 and CD8 T-cell responses. It also increases VLP- and VSV-G-specific antibody titres in a STING-dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS-CoV-2 Spike protein enhances Spike-specific antibody titres. cGAMP-loaded VLPs are thus an attractive platform for vaccination.


Assuntos
COVID-19 , Vacinas contra Influenza , Vacinas de Partículas Semelhantes a Vírus , Animais , Humanos , Camundongos , Nucleotídeos Cíclicos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Vacinas de Partículas Semelhantes a Vírus/genética
5.
J Virol ; 91(21)2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28835490

RESUMO

Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR- natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8+ T cells, but overall CD8+ T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control.IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection.


Assuntos
Infecções Assintomáticas/epidemiologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Vírus Epstein-Barr/virologia , Células Matadoras Naturais/imunologia , Adulto , Anticorpos Antivirais/sangue , DNA Viral/genética , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Reino Unido/epidemiologia , Carga Viral , Adulto Jovem
6.
Cytotherapy ; 16(10): 1409-18, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24969967

RESUMO

BACKGROUND AIMS: Graft-versus-host disease remains a major cause of death after hematopoietic stem cell transplantation. Cyclosporine (CsA) and mycophenolate mofetil (MMF) have been successfully used alone or in combination as prophylaxis for graft-versus-host disease. Although the effects of these drugs on T cells have been studied, little is known about the effects of both drugs on natural killer (NK) cells. We examined if the sensitivity of umbilical cord blood (CB) NK cells to MMF and/or CsA differs from their adult counterparts. METHODS: An approach that was based on flow cytometry and real-time polymerase chain reaction was used to assess the effects of MMF, CsA and the combination of both drugs on the viability, activation, proliferation and cytotoxicity of peripheral blood (PB) and CB NK cells after culture with interleukin-2. RESULTS: MMF alone or together with CsA induced cell death of CB NK cells but not of PB NK cells. MMF and CsA had differential effects on NK cell activation but significantly reduced proliferation of CB NK cells. MMF reduced perforin expression by PB NK cells, whereas CsA alone or together with MMF drastically decreased degranulation of CB and PB NK cells. However, neither affected cytokine secretion by PB and CB NK cells. CONCLUSIONS: This study showed that CB NK cells were more sensitive to MMF and CsA than were PB NK cells. MMF and CsA had significant effects on NK cells that could jeopardize the beneficial effects of NK cells after hematopoietic stem cell transplantation.


Assuntos
Ciclosporina/farmacologia , Sangue Fetal/citologia , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ácido Micofenólico/análogos & derivados , Adulto , Células Cultivadas , Feminino , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Recém-Nascido , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Ácido Micofenólico/farmacologia , Gravidez
7.
J Immunol ; 187(7): 3721-9, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21876034

RESUMO

Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders.


Assuntos
Diferenciação Celular/imunologia , Interleucina-2/metabolismo , Proteínas Proto-Oncogênicas c-maf/biossíntese , Transdução de Sinais/imunologia , Células Th2/metabolismo , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Separação Celular , Imunoprecipitação da Cromatina , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-2/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo , Células Th2/imunologia
8.
Cell Rep Med ; 2(3): 100207, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33763653

RESUMO

Interactions between B cells and CD4+ T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen Plasmodium falciparum merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01B adjuvant. We demonstrate that the protein/AS01B platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality. Furthermore, our data indicate a greater Th2/Tfh2 skew within the polyfunctional response elicited following vaccination with protein/AS01B as compared to a Th1/Tfh1 skew with viral vectors. These data highlight the impact of vaccine platform on the cTfh cell response driving humoral immunity, associating a high-magnitude, Th2-biased cTfh response with potent antibody production.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Proteínas de Transporte/imunologia , Imunidade Humoral/efeitos dos fármacos , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Adolescente , Adulto , Linfócitos B/citologia , Linfócitos B/imunologia , Proteínas de Transporte/administração & dosagem , Proteínas de Transporte/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/imunologia , Humanos , Imunogenicidade da Vacina , Interferon gama/genética , Interferon gama/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/genética , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Saponinas/administração & dosagem , Células T Auxiliares Foliculares/citologia , Células T Auxiliares Foliculares/imunologia , Células Th2/citologia , Células Th2/imunologia , Vacinação , Vacinas de Subunidades Antigênicas , Vaccinia virus/genética , Vaccinia virus/imunologia
9.
Front Immunol ; 11: 156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32132995

RESUMO

Natural Killer (NK) cells play an important role in antiviral defense and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline-encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position -21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, -21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of peripheral blood NK cells in a cohort of 36 African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position -21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and -C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV-1/HCMV co-infection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B -21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with -21M HLA-B alleles. Instead, our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.


Assuntos
Coinfecção/imunologia , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1 , Antígenos HLA-B/genética , Células Matadoras Naturais/imunologia , Polimorfismo Genético , Adulto , África/epidemiologia , Alelos , Células Cultivadas , Estudos de Coortes , Estudos Transversais , Infecções por Citomegalovirus/virologia , Feminino , Infecções por HIV/virologia , Humanos , Pessoa de Meia-Idade , Adulto Jovem
10.
Sci Rep ; 10(1): 13271, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764708

RESUMO

Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-h oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components in regulating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, BMAL1 and CLOCK activate rhythmic transcription of genes including the nuclear receptor REV-ERBα, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. The REV-ERB agonist SR9009 inhibited promoter activity of diverse HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic agonists to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock components in regulating HIV-1 replication.


Assuntos
Antivirais/farmacologia , Repetição Terminal Longa de HIV/efeitos dos fármacos , HIV-1/fisiologia , Pirrolidinas/farmacologia , Tiofenos/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Relógios Circadianos/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Células Jurkat , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/virologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Receptores dos Hormônios Tireóideos/metabolismo , Replicação Viral/efeitos dos fármacos , Produtos do Gene rev do Vírus da Imunodeficiência Humana/metabolismo
11.
Commun Biol ; 3(1): 376, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665623

RESUMO

Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular response to oxygen. Human immunodeficiency virus (HIV) infected cells within secondary lymphoid tissues exist in a low-oxygen or hypoxic environment in vivo. However, the majority of studies on HIV replication and latency are performed under laboratory conditions where HIFs are inactive. We show a role for HIF-2α in restricting HIV transcription via direct binding to the viral promoter. Hypoxia reduced tumor necrosis factor or histone deacetylase inhibitor, Romidepsin, mediated reactivation of HIV and inhibiting HIF signaling-pathways reversed this phenotype. Our data support a model where the low-oxygen environment of the lymph node may suppress HIV replication and promote latency. We identify a mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to control latent HIV-1.


Assuntos
HIV-1/fisiologia , Latência Viral/fisiologia , Replicação Viral/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Microambiente Celular , Citometria de Fluxo , Humanos , Hipóxia/metabolismo , Hipóxia/virologia , Tecido Linfoide/metabolismo , Tecido Linfoide/virologia , Oxigênio , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Transcrição Viral/fisiologia , Ativação Viral
12.
Immunohorizons ; 4(11): 713-728, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172842

RESUMO

Rab11 recycling endosomes are involved in immunological synaptic functions, but the roles of Rab11 family-interacting protein 5 (Rab11Fip5), one of the Rab11 effectors, in the immune system remain obscure. Our previous study demonstrated that RAB11FIP5 transcripts are significantly elevated in PBMCs from HIV-1-infected individuals, making broadly HIV-1-neutralizing Abs compared with those without broadly neutralizing Abs; however, the role of Rab11FiP5 in immune functions remains unclear. In this study, a RAB11FIP5 gene knockout (RAB11FIP5 -/-) mouse model was employed to study the role of Rab11Fip5 in immune responses. RAB11FIP5 -/- mice exhibited no perturbation in lymphoid tissue cell subsets, and Rab11Fip5 was not required for serum Ab induction following HIV-1 envelope immunization, Ab transcytosis to mucosal sites, or survival after influenza challenge. However, differences were observed in multiple transcripts, including cytokine genes, in lymphocyte subsets from envelope-immunized RAB11FIP5 -/- versus control mice. These included alterations in several genes in NK cells that mirrored observations in NKs from HIV-infected humans expressing less RAB11FIP5, although Rab11Fip5 was dispensable for NK cell cytolytic activity. Notably, immunized RAB11FIP5 -/- mice had lower IL4 expression in CD4+ T follicular helper cells and showed lower TNF expression in CD8+ T cells. Likewise, TNF-α production by human CD8+ T cells correlated with PBMC RAB11FIP5 expression. These observations in RAB11FIP5 -/- mice suggest a role for Rab11Fip5 in regulating cytokine responses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , Transcriptoma , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Infecções por HIV/fisiopatologia , HIV-1/patogenicidade , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Front Immunol ; 9: 474, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29616021

RESUMO

Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A- phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF- NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control.


Assuntos
Coinfecção/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Células Matadoras Naturais/imunologia , Adulto , Antígenos de Diferenciação/imunologia , Coinfecção/patologia , Infecções por Citomegalovirus/patologia , Infecções por HIV/patologia , Humanos , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Masculino
14.
Nat Rev Immunol ; 22(3): 145, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35087198
15.
Sci Adv ; 3(6): e1603032, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28691087

RESUMO

T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse. This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament lengths of two differently sized filamentous actin populations, wherein formin-mediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact with activating surfaces and no cytoskeletal rearrangements. Our work suggests that incipient signaling in T cells initiates global cytoskeletal rearrangements across the whole cell, including a stiffening process for possibly mechanically supporting contact formation at the immunological synapse interface as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions.


Assuntos
Actinas/metabolismo , Citoesqueleto , Sinapses Imunológicas/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Biomarcadores , Linhagem Celular , Rearranjo Gênico do Linfócito T , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
Nat Rev Immunol ; 21(3): 134, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33564149
17.
Sci Rep ; 6: 22097, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26915707

RESUMO

Graft versus Host Disease (GvHD) remains one of the main complications after hematopoietic stem cell transplantation (HSCT). Due to their ability to suppress effector cells, regulatory T cells (Tregs) have been proposed as a cellular therapy to prevent GvHD, however they also inhibit the functions of natural killer (NK) cells, key effectors of the Graft versus Leukemia effect. In this study, we have explored whether a Tregs therapy will also impact on NK cell differentiation. Using an in vitro model of hematopoietic stem cell (HSC) differentiation into NK cells, we found that activated Tregs led to a 90% reduction in NK cell numbers when added at the time of commitment to the NK cell lineage. This effect was contact dependent and was reversible upon Tregs depletion. The few NK cells that developed in these cultures were mature and exhibited normal functions. Furthermore, adoptive transfer of activated Tregs in rag(-/-) γc(-/-) mice abrogated HSC differentiation into NK cells thus confirming our in vitro findings. Collectively, these results demonstrate for the first time that activated Tregs can inhibit NK cell differentiation from HSC under specific conditions.


Assuntos
Proliferação de Células , Hematopoese , Células Matadoras Naturais/fisiologia , Linfócitos T Reguladores/fisiologia , Transferência Adotiva , Animais , Humanos , Células Matadoras Naturais/imunologia , Camundongos , Linfócitos T Reguladores/imunologia
18.
Sci Immunol ; 1(1): aag0851, 2016 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-28783677

RESUMO

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. bnAbs occur in some HIV-1-infected individuals and frequently have characteristics of autoantibodies. We have studied cohorts of HIV-1-infected individuals who made bnAbs and compared them with those who did not do so, and determined immune traits associated with the ability to produce bnAbs. HIV-1-infected individuals with bnAbs had a higher frequency of blood autoantibodies, a lower frequency of regulatory CD4+ T cells, a higher frequency of circulating memory T follicular helper CD4+ cells, and a higher T regulatory cell level of programmed cell death-1 expression compared with HIV-1-infected individuals without bnAbs. Thus, induction of HIV-1 bnAbs may require vaccination regimens that transiently mimic immunologic perturbations in HIV-1-infected individuals.

19.
PLoS One ; 9(1): e87086, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24489840

RESUMO

Adoptive natural killer (NK) cell therapy relies on the acquisition of large numbers of NK cells that are cytotoxic but not exhausted. NK cell differentiation from hematopoietic stem cells (HSC) has become an alluring option for NK cell therapy, with umbilical cord blood (UCB) and mobilized peripheral blood (PBCD34(+)) being the most accessible HSC sources as collection procedures are less invasive. In this study we compared the capacity of frozen or freshly isolated UCB hematopoietic stem cells (CBCD34(+)) and frozen PBCD34(+) to generate NK cells in vitro. By modifying a previously published protocol, we showed that frozen CBCD34(+) cultures generated higher NK cell numbers without loss of function compared to fresh CBCD34(+) cultures. NK cells generated from CBCD34(+) and PBCD34(+) expressed low levels of killer-cell immunoglobulin-like receptors but high levels of activating receptors and of the myeloid marker CD33. However, blocking studies showed that CD33 expression did not impact on the functions of the generated cells. CBCD34(+)-NK cells exhibited increased capacity to secrete IFN-γ and kill K562 in vitro and in vivo as compared to PBCD34(+)-NK cells. Moreover, K562 killing by the generated NK cells could be further enhanced by IL-12 stimulation. Our data indicate that the use of frozen CBCD34(+) for the production of NK cells in vitro results in higher cell numbers than PBCD34(+), without jeopardizing their functionality, rendering them suitable for NK cell immunotherapy. The results presented here provide an optimal strategy to generate NK cells in vitro for immunotherapy that exhibit enhanced effector function when compared to alternate sources of HSC.


Assuntos
Citotoxicidade Imunológica , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/citologia , Células Matadoras Naturais/citologia , Transferência Adotiva , Animais , Antígenos CD34/genética , Antígenos CD34/imunologia , Biomarcadores/metabolismo , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Criopreservação , Sangue Fetal/imunologia , Expressão Gênica , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Humanos , Interferon gama/biossíntese , Interferon gama/metabolismo , Interleucina-12/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Camundongos , Camundongos Endogâmicos NOD , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
20.
Cell Mol Immunol ; 10(3): 222-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23524654

RESUMO

Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.


Assuntos
Comunicação Celular/imunologia , Imunoterapia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Feminino , Humanos , Modelos Imunológicos , Gravidez
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