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1.
Eur J Immunol ; 45(10): 2945-58, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26179882

RESUMO

Human cytomegalovirus (CMV) induces the formation of effector CD8(+) T cells that are maintained for decades during the latent stage of infection. Effector CD8(+) T cells appear quiescent, but maintain constitutive cytolytic capacity and can immediately produce inflammatory cytokines such as IFN-γ after stimulation. It is unclear how effector CD8(+) T cells can be constitutively maintained in a terminal stage of effector differentiation in the absence of overt viral replication. We have recently described the zinc finger protein Homolog of Blimp-1 in T cells (Hobit) in murine NKT cells. Here, we show that human Hobit was uniformly expressed in effector-type CD8(+) T cells, but not in naive or in most memory CD8(+) T cells. Human CMV-specific but not influenza-specific CD8(+) T cells expressed high levels of Hobit. Consistent with the high homology between the DNA-binding Zinc Finger domains of Hobit and Blimp-1, Hobit displayed transcriptional activity at Blimp-1 target sites. Expression of Hobit strongly correlated with T-bet and IFN-γ expression within the CD8(+) T-cell population. Furthermore, Hobit was both necessary and sufficient for the production of IFN-γ. These data implicate Hobit as a novel transcriptional regulator in quiescent human effector-type CD8(+) T cells that regulates their immediate effector functions.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Interferon gama/imunologia , Proteínas Repressoras/imunologia , Animais , Linhagem Celular , Humanos , Vírus da Influenza A/imunologia , Interferon gama/genética , Camundongos , Células T Matadoras Naturais/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
2.
J Clin Invest ; 120(11): 4077-90, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20921622

RESUMO

CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human cytomegalovirus (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-γ-regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Diferenciação Celular/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/citologia , Separação Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Ativação Linfocitária/imunologia , Análise em Microsséries , Latência Viral
3.
J Immunol ; 181(9): 5847-56, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18941173

RESUMO

Jakmip1 belongs to a family of three related genes encoding proteins rich in coiled-coils. Jakmip1 is expressed predominantly in neuronal and lymphoid cells and colocalizes with microtubules. We have studied the expression of Jakmip1 mRNA and protein in distinct subsets of human primary lymphocytes. Jakmip1 is absent in naive CD8(+) and CD4(+) T lymphocytes from peripheral blood but is highly expressed in Ag-experienced T cells. In cord blood T lymphocytes, induction of Jakmip1 occurs upon TCR/CD28 stimulation and parallels induction of effector proteins, such as granzyme B and perforin. Further analysis of CD8(+) and CD4(+) T cell subsets showed a higher expression of Jakmip1 in the effector CCR7(-) and CD27(-) T cell subpopulations. In a gene expression follow-up of the development of CMV-specific CD8(+) response, Jakmip1 emerged as one of the most highly up-regulated genes from primary infection to latent stage. To investigate the relationship between Jakmip1 and effector function, we monitored cytotoxicity of primary CD8(+) T cells silenced for Jakmip1 or transduced with the full-length protein or the N-terminal region. Our findings point to Jakmip1 being a novel effector memory gene restraining T cell-mediated cytotoxicity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Diferenciação Celular/imunologia , Citotoxicidade Imunológica , Inibidores do Crescimento/fisiologia , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Morte Celular/genética , Morte Celular/imunologia , Diferenciação Celular/genética , Linhagem Celular , Citomegalovirus/imunologia , Citotoxicidade Imunológica/genética , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/deficiência , Inibidores do Crescimento/genética , Humanos , Memória Imunológica/genética , Antígenos Comuns de Leucócito/biossíntese , Proteínas de Ligação a RNA/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/virologia
4.
J Immunol ; 180(7): 4550-60, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18354177

RESUMO

The CD8(+) T cell compartment of human CMV-seropositive individuals characteristically contains a high proportion of cells that express NK cell receptors (NKRs) which may contribute to the surveillance of virus-infected cells. To test whether this enhanced expression is a direct and immediate result of CMV infection, we used DNA microarrays to analyze putative changes in the RNA expression level of 39 NKRs in CMV-specific CD8(+) T cells of renal transplant recipients experiencing primary CMV infection. Already in the acute phase of infection 29 NKRs were induced, of which 19 remained high 1 year after cessation of viral replication. Activating and inhibitory NKRs were induced to a similar extent. Detailed longitudinal flow cytometric analyses confirmed NKR changes at the protein level. Strikingly, a strong induction of CD94 on CD3(+) T cells was observed with surface expression of activating CD94(dim) NKG2C dimers appearing before inhibitory CD94(bright) NKG2A ones. After the acute phase of infection, the balance between inhibitory and activating receptors did not change. Thus, CMV infection induces a rapid and lasting change in the expression of NKRs on human CD8(+) T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por Citomegalovirus/imunologia , Regulação da Expressão Gênica , Células Matadoras Naturais/imunologia , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Adulto , Idoso , Dimerização , Humanos , Cinética , Pessoa de Meia-Idade , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo
5.
J Clin Virol ; 41(3): 213-7, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18061537

RESUMO

Latent infection with human cytomegalovirus (HCMV) is accompanied by a strong increase in the number of resting, effector-type CD4+ and CD8+ T cells with constitutive cytolytic activity in the circulation. Longitudinal studies in kidney transplant recipients revealed that effector cells emerge early after the initial viral burst and acquire their stable phenotype in the months following primary infection. Although it is yet unsettled whether these cells are all specific for CMV encoded or induced antigens, it has become clear that T cell responses to CMV are among the broadest and strongest analyzed so far. We will here summarize the qualities of the effector-type cells found in HCMV carriers and discuss their possible role in CMV-associated pathologies.


Assuntos
Aterosclerose/virologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Aterosclerose/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Humanos
6.
Clin Cancer Res ; 11(7): 2540-6, 2005 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15814631

RESUMO

PURPOSE: Apoptosis is an important mechanism regulating survival of acute myeloid leukemia cells. The apoptosis-related protein profile at diagnosis is important for achieving complete remission thereby affecting survival variables such as disease-free survival (DFS) and overall survival (OS).To investigate the role of the apoptosis protein profile in further response to therapy and outgrowth of disease. EXPERIMENTAL DESIGN: We studied whether Bcl-2, Bcl-xL, Mcl-1, Bax as well as the Bcl-2/Bax ratio and a combination of all (antiapoptosis index, AAI) are related to the frequency of malignant cells surviving the chemotherapy (i.e., minimal residual disease, MRD). MRD cells were identified by leukemia-associated aberrant phenotypes established at diagnosis by flow cytometry. RESULTS: We found that Bcl-2 (R = 0.55, P = 0.002), Bcl-2/Bax (R = 0.42, P = 0.02), and AAI (R = 0.47, P = 0.01) at diagnosis directly correlated with MRD after the first cycle of chemotherapy. In turn, MRD frequency after first cycle correlated with DFS (P = 0.04). Taken together, these results directly explain why Bcl-2/Bax and especially AAI (P = 0.007) at diagnosis correlate with DFS. CONCLUSION: Our results show that apoptosis resistance plays an important role in the first stage of the therapy (i.e., to eliminate the bulk of malignant cells), in terms of achievement of complete remission and frequency of MRD after first cycle of therapy.


Assuntos
Apoptose , Biomarcadores Tumorais/análise , Leucemia Mieloide/diagnóstico , Neoplasia Residual/diagnóstico , Doença Aguda , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/análise , Neoplasia Residual/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteína X Associada a bcl-2 , Proteína bcl-X
7.
Haematologica ; 88(5): 497-508, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12745269

RESUMO

BACKGROUND AND OBJECTIVES: Altered expression of members of the Bcl-2 family might account for the observed apoptosis resistance to chemotherapy in acute myeloid leukemia (AML). Given the poor prognosis associated with CD34+ expression in AML, we studied the role of spontaneous apoptosis and apoptosis regulatory proteins in sorted CD34+ and CD34- primary AML fractions. DESIGN AND METHODS: The expression levels of apoptosis regulatory proteins and spontaneous apoptosis were measured in primary AML samples by Western blot analysis and flow cytometry. To determine the role of CD34+ cells in apoptosis resistance, spontaneous apoptosis in serum-free conditions and apoptosis regulatory protein levels were measured in CD34+ and CD34- sorted cells from CD34+ primary AML samples. RESULTS: We show that CD34+ AML fractions are more resistant to apoptosis than are corresponding CD34- AML fractions, and that this is paralleled by higher Bcl-2, Bcl-xL, Mcl-1, Pgp and lower Bax expression levels. Interestingly, as the percentage of CD34 cells increased in the primary AML sample, so too did the apoptosis resistance in the corresponding CD34- fraction, which was reflected by an increasing anti-apoptosis protein profile. INTERPRETATION AND CONCLUSIONS: The data show that the CD34+ fraction is more resistant to apoptosis than is the corresponding CD34- fraction and secondly that the AML as a whole is more apoptosis resistant with increasing CD34 percentage.


Assuntos
Antígenos CD34/análise , Apoptose , Leucemia Mieloide/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Doença Aguda , Antígenos CD/análise , Antígenos CD34/metabolismo , Citometria de Fluxo , Humanos , Leucemia Mieloide/classificação , Leucemia Mieloide/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células Tumorais Cultivadas , Proteína X Associada a bcl-2 , Proteína bcl-X
8.
Vet Immunol Immunopathol ; 85(1-2): 9-22, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11867163

RESUMO

The characteristics of a feline homologue of the alphaE integrin (CD103), defined by two murine monoclonal antibodies, Fe7.1B8 (IgG1) and Fe7.2D8 (IgG1), are described. These antibodies recognized 75% of intra-epithelial (range 59-88%) and 40% of lamina proprial (range 28-46%) T cells of the intestinal mucosal tissue of the small intestine in contrast with approximately 2% of peripheral blood lymphocytes. Both antibodies immunoprecipitated a 180 kDa protein from biotinylated feline intra-epithelial mucosal leukocytes consistent with the alphaE integrin subunit in conjunction with a 120 kDa protein consistent with the beta7 subunit. The nucleotide sequence of feline alphaE integrin, generated from molecular cloning of the feline alphaE encoding cDNA, is also reported. This feline molecule shares 72% sequence homology with human and 69% homology with murine and rat counterparts. Homology includes the presence of an X (extra) domain, that appears unique to alphaE molecules as described for human, rat and mouse, as well as areas of homology common to other alpha integrins. Of note is a typical I (inserted) domain, the presence of seven repeat regions, and highly conserved sequences in the cytoplasmic tail. Transfection studies demonstrated that both antibodies recognized an extracellular component which encompassed the X and I domains of the cloned alphaE integrin subunit. These studies demonstrate that the pattern of tissue distribution, biochemical characteristics, and cDNA sequence of the feline alphaE integrin subunit are largely similar to that described for other species.


Assuntos
Antígenos CD/análise , Gatos/imunologia , Cadeias alfa de Integrinas , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD/química , Antígenos CD/imunologia , Células COS , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Testes de Precipitina
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