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1.
Sci Immunol ; 6(57)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653907

RESUMO

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.


Assuntos
/imunologia , Ativação Linfocitária , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Envelhecimento/imunologia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Leucopenia/imunologia , Masculino , Adulto Jovem
2.
Cell ; 184(7): 1858-1864.e10, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631096

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the coronavirus disease 2019 (COVID-19) pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 431 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 251 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼20% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.


Assuntos
Alphacoronavirus/imunologia , Anticorpos Antivirais , Betacoronavirus/imunologia , /imunologia , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Criança , Pré-Escolar , Chlorocebus aethiops , Proteção Cruzada , Reações Cruzadas , Suscetibilidade a Doenças , Células HEK293 , Humanos , Lactente , Recém-Nascido , Células Vero
3.
Cell ; 184(5): 1262-1280.e22, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33636129

RESUMO

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.

4.
medRxiv ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33200143

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread within the human population. Although SARS-CoV-2 is a novel coronavirus, most humans had been previously exposed to other antigenically distinct common seasonal human coronaviruses (hCoVs) before the COVID-19 pandemic. Here, we quantified levels of SARS-CoV-2-reactive antibodies and hCoV-reactive antibodies in serum samples collected from 204 humans before the COVID-19 pandemic. We then quantified pre-pandemic antibody levels in serum from a separate cohort of 252 individuals who became PCR-confirmed infected with SARS-CoV-2. Finally, we longitudinally measured hCoV and SARS-CoV-2 antibodies in the serum of hospitalized COVID-19 patients. Our studies indicate that most individuals possessed hCoV-reactive antibodies before the COVID-19 pandemic. We determined that ∼23% of these individuals possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but paradoxically these hCoV cross-reactive antibodies were boosted upon SARS-CoV-2 infection.

5.
medRxiv ; 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32995826

RESUMO

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.

6.
Science ; 369(6508)2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32669297

RESUMO

Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.


Assuntos
Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Subpopulações de Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/sangue , Feminino , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Plasmócitos/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Tempo , Adulto Jovem
7.
bioRxiv ; 2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32511371

RESUMO

COVID-19 has become a global pandemic. Immune dysregulation has been implicated, but immune responses remain poorly understood. We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ~200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three "immunotypes" associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.

8.
Immunity ; 51(5): 840-855.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31606264

RESUMO

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Fator 1 de Transcrição de Linfócitos T/genética , Viroses/genética , Viroses/imunologia , Viroses/virologia
9.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Genética , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
11.
Nat Immunol ; 17(8): 976-84, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27376469

RESUMO

Follicular helper T cells (TFH cells) are CD4(+) T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting TFH cells therapeutically has been limited by fragmentary understanding of extrinsic signals that regulate the differentiation of human TFH cells. A screen of a human protein library identified activin A as a potent regulator of TFH cell differentiation. Activin A orchestrated the expression of multiple genes associated with the TFH program, independently or in concert with additional signals. TFH cell programming by activin A was antagonized by the cytokine IL-2. Activin A's ability to drive TFH cell differentiation in vitro was conserved in non-human primates but not in mice. Finally, activin-A-induced TFH programming was dependent on signaling via SMAD2 and SMAD3 and was blocked by pharmacological inhibitors.


Assuntos
Ativinas/metabolismo , Centro Germinativo/imunologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Evolução Biológica , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Primatas , Transdução de Sinais , Especificidade da Espécie
12.
J Immunol ; 197(3): 994-1002, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27335502

RESUMO

A range of current candidate AIDS vaccine regimens are focused on generating protective HIV-neutralizing Ab responses. Many of these efforts rely on the rhesus macaque animal model. Understanding how protective Ab responses develop and how to increase their efficacy are both major knowledge gaps. Germinal centers (GCs) are the engines of Ab affinity maturation. GC T follicular helper (Tfh) CD4 T cells are required for GCs. Studying vaccine-specific GC Tfh cells after protein immunizations has been challenging, as Ag-specific GC Tfh cells are difficult to identify by conventional intracellular cytokine staining. Cytokine production by GC Tfh cells may be intrinsically limited in comparison with other Th effector cells, as the biological role of a GC Tfh cell is to provide help to individual B cells within the GC, rather than secreting large amounts of cytokines bathing a tissue. To test this idea, we developed a cytokine-independent method to identify Ag-specific GC Tfh cells. RNA sequencing was performed using TCR-stimulated GC Tfh cells to identify candidate markers. Validation experiments determined CD25 (IL-2Rα) and OX40 to be highly upregulated activation-induced markers (AIM) on the surface of GC Tfh cells after stimulation. In comparison with intracellular cytokine staining, the AIM assay identified >10-fold more Ag-specific GC Tfh cells in HIV Env protein-immunized macaques (BG505 SOSIP). CD4 T cells in blood were also studied. In summary, AIM demonstrates that Ag-specific GC Tfh cells are intrinsically stingy producers of cytokines, which is likely an essential part of their biological function.


Assuntos
Biomarcadores/análise , Infecções por HIV/imunologia , Técnicas Imunológicas/métodos , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Citocinas/análise , Citocinas/biossíntese , Modelos Animais de Doenças , Citometria de Fluxo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Macaca mulatta
13.
Proc Natl Acad Sci U S A ; 113(10): 2702-7, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26908875

RESUMO

Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS(+) (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.


Assuntos
Biomarcadores/sangue , Quimiocina CXCL13/sangue , Quimiocina CXCL13/imunologia , Centro Germinativo/imunologia , Animais , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Infecções por HIV/sangue , Infecções por HIV/imunologia , Humanos , Linfonodos/imunologia , Macaca , Camundongos Endogâmicos C57BL , Vacinação
14.
PLoS One ; 8(5): e64702, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23717651

RESUMO

Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART) is largely based on CD4+ T cell counts and viral load, measures that fail to take into account the CD8+ T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase (ADA), glucose uptake receptor 1 (GLUT1), and leucine-rich repeat neuronal 3 (LRRN3) to CD38 expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced ADA, telomerase activity and LRRN3 gene expression were significantly associated with high CD38 and HLA-DR in CD8+ T cells, with % ADA+ cells being the most robust predictor of CD8+ T cell activation. Our results suggest that ADA, LRRN3 and telomerase activity in CD8+ T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8+ T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8+ T cells, the prolonged survival and resultant increased age of the HIV+ population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.


Assuntos
Envelhecimento/patologia , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por HIV/patologia , Sequência de Bases , Primers do DNA , Citometria de Fluxo , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real
15.
J Clin Immunol ; 30(6): 798-805, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20721608

RESUMO

CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.


Assuntos
Envelhecimento/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Infecções por HIV/imunologia , Animais , Antígenos CD28/genética , Antígenos CD28/imunologia , Progressão da Doença , Regulação da Expressão Gênica/imunologia , Humanos , Transdução de Sinais/imunologia
16.
J Immunol ; 184(6): 2847-54, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20147632

RESUMO

Increased proportions of CD8 T lymphocytes lacking expression of the CD28 costimulatory receptor have been documented during both aging and chronic infection with HIV-1, and their abundance correlates with numerous deleterious clinical outcomes. CD28-negative cells also arise in cell cultures of CD8(+)CD28(+) following multiple rounds of Ag-driven proliferation, reaching the end stage of replicative senescence. The present study investigates the role of a second T cell costimulatory receptor component, adenosine deaminase (ADA), on the process of replicative senescence. We had previously reported that CD28 signaling is required for optimal telomerase upregulation. In this study, we show that the CD8(+)CD28(+) T lymphocytes that are ADA(+) have significantly greater telomerase activity than those that do not express ADA and that ADA is progressively lost as cultures progress to senescence. Because ADA converts adenosine to inosine, cells lacking this enzyme might be subject to prolonged exposure to adenosine, which has immunosuppressive effects. Indeed, we show that chronic exposure of CD8 T lymphocytes to exogenous adenosine accelerates the process of replicative senescence, causing a reduction in overall proliferative potential, reduced telomerase activity, and blunted IL-2 gene transcription. The loss of CD28 expression was accelerated, in part due to adenosine-induced increases in constitutive caspase-3, known to act on the CD28 promoter. These findings provide the first evidence for a role of ADA in modulating the process of replicative senescence and suggest that strategies to enhance this enzyme may lead to novel therapeutic approaches for pathologies associated with increases in senescent CD8 T lymphocytes.


Assuntos
Adenosina Desaminase/fisiologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/enzimologia , Divisão Celular/imunologia , Senescência Celular/imunologia , Telomerase/metabolismo , Adenosina/farmacologia , Adenosina Desaminase/biossíntese , Inibidores de Adenosina Desaminase , Antígenos CD28/biossíntese , Antígenos CD28/metabolismo , Antígenos CD8/biossíntese , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Células Cultivadas , Regulação para Baixo/imunologia , Ativação Enzimática/imunologia , Infecções por HIV/enzimologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Telomerase/antagonistas & inibidores , Regulação para Cima/imunologia
17.
J Immunol ; 182(7): 4237-43, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19299722

RESUMO

Expanded populations of CD8(+) T lymphocytes lacking CD28 expression are associated with a variety of deleterious clinical outcomes, including early mortality in the elderly, more rapid progression to AIDS, cardiovascular disease, and enhanced tumor cell growth. In cell culture, irreversible loss of CD28 expression correlates with increased production of TNF-alpha as CD8(+) T cells are driven to the nonproliferative end stage of replicative senescence by multiple rounds of Ag-driven cell division. Interestingly, in patients with rheumatoid arthritis, inhibition or neutralization of TNF-alpha reduces the proportion of T cells lacking CD28 in the disease joints, consistent with studies showing a direct involvement of this cytokine in CD28 gene transcription. Here, we show that modulation of TNF-alpha levels in long-term cultures of human CD8(+) T lymphocytes, by chronic exposure either to a neutralizing Ab or to an inhibitor of the TNF-alpha receptor-1, increases proliferative potential, delays loss of CD28 expression, retards cytokine profile changes, and enhances telomerase activity. We also show that constitutive caspase-3, one of the downstream effectors of TNF-alphaR1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNF-alpha inhibitors. Consistent with the in vitro culture data, CD8(+)CD28(-) T lymphocytes tested immediately ex vivo also show significantly higher levels of caspase-3 compared with their CD28(+) counterparts. These findings help elucidate the complex nature of CD28 gene regulation, and may ultimately lead to novel therapeutic approaches for diseases associated with increased proportions of CD28(-) T lymphocytes.


Assuntos
Antígenos CD28/biossíntese , Linfócitos T CD8-Positivos/imunologia , Caspase 3/imunologia , Senescência Celular/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antígenos CD28/genética , Antígenos CD28/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Caspase 3/metabolismo , Proliferação de Células , Células Cultivadas , Senescência Celular/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Telomerase/metabolismo , Fator de Necrose Tumoral alfa/imunologia
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