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1.
Immunity ; 51(6): 1059-1073.e9, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757674

RESUMO

Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand (PD-L1) exhibits superior anti-tumor responses compared with single-agent therapy. Here, we examined the molecular basis for this synergy. Using reconstitution assays with fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerize in cis but not trans. Quantitative biochemistry and cell biology assays revealed that PD-L1:CD80 cis-heterodimerization inhibited both PD-L1:PD-1 and CD80:CTLA-4 interactions through distinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatory receptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) prevented CTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surface expression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 with ipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy.


Assuntos
Antígeno B7-1/metabolismo , Antígeno B7-H1/metabolismo , Antígenos CD28/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia/métodos , Ipilimumab/farmacologia , Células Jurkat , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
2.
Adv Exp Med Biol ; 1189: 3-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758529

RESUMO

The two-signal model of T-cell activation, proposed approximately four decades ago, has undergone various refinements while maintaining its principal doctrine. Since the discovery of CD28, a variety of co-signal molecules, including co-stimulatory and co-inhibitory receptors and ligands, have been identified. These molecules fine-tune various immune responses both in the primary or secondary lymphoid tissues and in the peripheral tissues. Most co-signal receptors are expressed and induced on T cells during distinct stages (naïve/resting, activating, memory, and exhausting). These co-signaling pathways play critical and diverse roles in maintaining T-cell tolerance and eliciting T-cell immune responses in health and disease. This introductory chapter provides a historical overview of the key findings that have led to our current view of T-cell co-stimulation.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia , Humanos , Tolerância Imunológica
3.
Adv Exp Med Biol ; 1189: 25-51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758530

RESUMO

Immune responses are controlled by the optimal balance between protective immunity and immune tolerance. T-cell receptor (TCR) signals are modulated by co-signaling molecules, which are divided into co-stimulatory and co-inhibitory molecules. By expression at the appropriate time and location, co-signaling molecules positively and negatively control T-cell differentiation and function. For example, ligation of the CD28 on T cells provides a critical secondary signal along with TCR ligation for naive T-cell activation. In contrast, co-inhibitory signaling by the CD28-B7 family is important to regulate immune homeostasis and host defense, as these signals limit the strength and duration of immune responses to prevent autoimmunity. At the same time, microorganisms or tumor cells can use these pathways to establish an immunosuppressive environment to inhibit the immune responses against themselves. Understanding these co-inhibitory pathways will support the development of new immunotherapy for the treatment of tumors and autoimmune and infectious diseases. Here, we introduce diverse molecules belonging to the members of the CD28-B7 family.


Assuntos
Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Ativação Linfocitária , Transdução de Sinais , Linfócitos T/citologia , Humanos , Tolerância Imunológica , Imunoterapia
4.
Adv Exp Med Biol ; 1189: 85-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758532

RESUMO

T-cell receptor (TCR)-mediated antigen-specific stimulation is essential for initiating T-cell activation. However, signaling through the TCR alone is not sufficient for inducing an effective response. In addition to TCR-mediated signaling, signaling through antigen-independent co-stimulatory or co-inhibitory receptors is critically important not only for the full activation and functional differentiation of T cells but also for the termination and suppression of T-cell responses. Many studies have investigated the signaling pathways underlying the function of each molecular component. Co-stimulatory and co-inhibitory receptors have no kinase activity, but their cytoplasmic region contains unique functional motifs and potential phosphorylation sites. Engagement of co-stimulatory receptors leads to recruitment of specific binding partners, such as adaptor molecules, kinases, and phosphatases, via recognition of a specific motif. Consequently, each co-stimulatory receptor transduces a unique pattern of signaling pathways. This review focuses on our current understanding of the intracellular signaling pathways provided by co-stimulatory and co-inhibitory molecules, including B7:CD28 family members, immunoglobulin, and members of the tumor necrosis factor receptor superfamily.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Humanos , Imunoglobulinas/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo
5.
Adv Exp Med Biol ; 1189: 135-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758533

RESUMO

T-cell activation is induced through the TCR microcluster (TCR-MC), which is generated by dynamically recruiting the TCR, kinases, and adaptors to trigger the full activation signal. Co-stimulation receptors also accumulate, mostly at the TCR-MC, and induce signals that positively and negatively modulate the direction and magnitude of T-cell activation. CD28 initially colocalizes with the TCR-MC but then migrates to a distinct region of the cSMAC called the signaling cSMAC, where it recruits and associates with PKCθ, CARMA1, and Rltpr to induce sustained co-stimulation signals leading to NF-kB activation. Although CTLA-4 and PD-1 mediate inhibitory functions in T-cell activation, their molecular dynamics are quite different. Both are expressed only after activation, when they function as feedback inhibition of T-cell activation. Whereas PD-1 initially accumulates in the TCR-MC and then moves to the cSMAC, CTLA-4 directly accumulates at the cSMAC. PD-1 inhibits activation by inducing dephosphorylation of TCR-upstream signaling molecules by transiently recruiting SHP2, whereas CTLA-4 competes with CD28 for CD80/86 binding within the signaling cSMAC. In general, for both positive and negative co-stimulation, these co-stimulation receptors are also clustered in a ligand-dependent fashion, and their colocalization with the TCR-MC is required to mediate co-stimulation signals.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Humanos
6.
Adv Exp Med Biol ; 1189: 213-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758536

RESUMO

Co-receptors cooperatively regulate the function of immune cells to optimize anti-infectious immunity while limiting autoimmunity by providing stimulatory and inhibitory co-signals. Among various co-receptors, those in the CD28/CTLA-4 family play fundamental roles in the regulation of lymphocytes by modulating the strength, quality, and/or duration of the antigen receptor signal. The development of the lethal lymphoproliferative disorder and various tissue-specific autoimmune diseases in mice deficient for CTLA-4 and PD-1, respectively, clearly demonstrates their pivotal roles in the development and the maintenance of immune tolerance. The recent success of immunotherapies targeting CTLA-4 and PD-1 in the treatment of various cancers highlights their critical roles in the regulation of cancer immunity in human. In addition, the development of multifarious autoimmune diseases as immune-related adverse events of anti-CTLA-4 and anti-PD-1/PD-L1 therapies and the successful clinical application of the CD28 blocking therapy using CTLA-4-Ig to the treatment of arthritis assure their crucial roles in the regulation of autoimmunity in human. Accumulating evidences in mice and humans indicate that genetic and environmental factors strikingly modify effects of the targeted inhibition and potentiation of co-signals. In this review, we summarize our current understanding of the roles of CD28, CTLA-4, and PD-1 in autoimmunity. Deeper understandings of the context-dependent and context-independent functions of co-signals are essential for the appropriate usage and the future development of innovative immunomodulatory therapies for a diverse array of diseases.


Assuntos
Autoimunidade , Antígenos CD28/metabolismo , Antígeno CTLA-4/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Humanos , Tolerância Imunológica , Imunoterapia , Camundongos
7.
Mol Immunol ; 112: 387-393, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288148

RESUMO

Programmed cell death 4 (Pdcd4) was found to be related to apoptosis upon first discovery. It was later found to play the role of tumor suppressor gene in a variety of tumors by inhibiting transcription and translation. Recently, it has been proposed that it may play an important role in some inflammatory diseases and in the immune response. In our previous study, deficiency of Pdcd4 was found to attenuate the formation of atherosclerotic plaques. This might be because deficiency of Pdcd4 may increase IL-10 expression and lipoautophagy by macrophages and attenuate the formation of foam cells. However, the effect of Pdcd4 on the subsets of T cells in hyperlipidemic mice still remained unclear. In the present study, results showed that Pdcd4 deficiency decreased the percentage of CD8+ T cells and increased that of regulatory T cells (Tregs) under hyperlipidemic conditions both in vitro and in vivo, which may be due to the reduced expression of co-stimulatory molecules CD28 and CD137, and the enhancive expression of co-inhibitory molecules CTLA-4. These results indicated that endogenous Pdcd4 promotes immune response mediated by T cells through regulation of the co-stimulatory molecules expression, which may contribute to the development of advanced atherosclerotic plaques. The current work provides new data to understand the role of Pdcd4 in different T cell subsets under hyperlipidemic microenvironment.


Assuntos
Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Hiperlipidemias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Subpopulações de Linfócitos T/metabolismo , Animais , Apoptose/fisiologia , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Espumosas/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
8.
Scand J Immunol ; 90(3): e12802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269269

RESUMO

Glucose and nutrient uptake is essential in supporting T cell activation and is increased upon CD3/CD28 stimulation. As T cells from pleural effusions secondary to lung cancer show impaired function, we hypothesized that these cells might have altered expression of nutrient transporters. Here, we analysed by flow cytometry the expression of the transferrin receptor CD71, amino acid transporter CD98 and glucose transporter Glut1 and glucose uptake in pleural effusion-derived T cells from lung cancer patients, after stimulation via CD3/CD28 under normoxia or hypoxia (2% O2 ). We compared the response of T cells from pleural effusions secondary to lung cancer with that of T cells from nonmalignant effusions. In memory T cells from both groups, anti-CD3/CD28-stimulation under normoxia upregulated CD98 and CD71 expression (measured as median fluorescence intensity, MFI) in comparison with anti-CD3-stimulation. Costimulation under hypoxia tended to increase CD98 expression compared to CD3-stimulation in memory T cells from both groups. Remarkably, in the cancer group, memory T cells stimulated via CD3/CD28 under hypoxia failed to increase CD71 and Glut1 expression levels compared to the cells receiving anti-CD3 stimulation, a phenomenon that contrasted with the behaviour of memory T cells from nonmalignant effusions. Consequently, glucose uptake by memory T cells from the cancer group was not increased after CD3/CD28 stimulation under hypoxia, implying that their glycolytic metabolism is defective. As this process is required for inducing an antitumoural response, our study suggests that memory T cells are rendered dysfunctional and are unable to eliminate lung tumour cells.


Assuntos
Antígenos CD28/metabolismo , Complexo CD3/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Memória Imunológica/imunologia , Neoplasias Pulmonares/metabolismo , Derrame Pleural/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Linfócitos T/metabolismo
9.
Cells ; 8(6)2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212712

RESUMO

The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro-inflammatory T cell functions in relapsing-remitting MS (RRMS) patients. We show that CD28 up-regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c-myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3-kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS.


Assuntos
Antígenos CD28/metabolismo , Glicólise , Inflamação/patologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Linfócitos T/imunologia , Regulação para Cima , Adulto , Idoso , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Humanos , Metabolômica , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/metabolismo
10.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181772

RESUMO

Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized-tolerance, anergy, exhaustion, and senescence-CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28- senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28- senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunossenescência , Neoplasias/imunologia , Animais , Antígenos CD28/genética , Antígenos CD28/metabolismo , Humanos , Imunoterapia/métodos , Neoplasias/terapia
11.
Dis Markers ; 2019: 5421985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089395

RESUMO

Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Antígenos CD28/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Imunoglobulinas/genética , Neoplasias Bucais/genética , Biomarcadores Tumorais/metabolismo , Antígenos CD28/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imunoglobulinas/metabolismo , Masculino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia
12.
Science ; 364(6440): 558-566, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31000591

RESUMO

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.


Assuntos
Antígeno B7-1/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Animais , Autoimunidade , Antígeno B7-1/genética , Antígenos CD28/metabolismo , Células Dendríticas/imunologia , Técnicas de Introdução de Genes , Humanos , Imunoterapia , Ativação Linfocitária , Camundongos , Camundongos Mutantes , Neoplasias/terapia , Ligação Proteica
13.
J Immunol ; 202(11): 3226-3233, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31010850

RESUMO

Clonal deletion of T cells specific for self-antigens in the thymus has been widely studied, primarily by approaches that focus on a single receptor (using TCR transgenes) or a single specificity (using peptide-MHC tetramers). However, less is known about clonal deletion at the population level. In this article, we report an assay that measures cleaved caspase 3 to define clonal deletion at the population level. This assay distinguishes clonal deletion from apoptotic events caused by neglect and approximates the anatomic site of deletion using CCR7. This approach showed that 78% of clonal deletion events occur in the cortex in mice. Medullary deletion events were detected at both the semimature and mature stages, although mature events were associated with failed regulatory T cell induction. Using this assay, we showed that bone marrow-derived APC drive approximately half of deletion events at both stages. We also found that both cortical and medullary deletion rely heavily on CD28 costimulation. These findings demonstrate a useful strategy for studying clonal deletion within the polyclonal repertoire.


Assuntos
Células da Medula Óssea/imunologia , Caspase 3/metabolismo , Deleção Clonal , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/imunologia , Animais , Apresentação do Antígeno , Apoptose , Autoantígenos/imunologia , Antígenos CD28/metabolismo , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteólise , Receptores CCR7 , Transdução de Sinais
14.
Monoclon Antib Immunodiagn Immunother ; 38(2): 60-69, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31009338

RESUMO

CD28 superagonist (CD28SA), a therapeutic immunomodulatory monoclonal antibody triggered rapid and exaggerated activation of CD4+ effector memory T cells (TEMs) in humans with unwanted serious adverse effects. It is well known that distinct metabolic programs determine the fate and responses of immune cells. In this study, we show that human CD4+ TEMs stimulated with CD28SA adopt a metabolic program similar to those of tumor cells with enhanced glucose utilization, lipid biosynthesis, and proliferation in hypoxic conditions. Identification of metabolic profiles underlying hyperactive T cell activation would provide a platform to test safety of immunostimulatory antibodies.


Assuntos
Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Glicólise/imunologia , Lipogênese/imunologia , Ativação Linfocitária/imunologia , Neoplasias/metabolismo , Acetilcoenzima A/metabolismo , Anticorpos Monoclonais/imunologia , Antígenos CD28/metabolismo , Proliferação de Células , Glucose/metabolismo , Humanos , Memória Imunológica , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Quinases/metabolismo , Linfócitos T Reguladores/imunologia , Células Tumorais Cultivadas
15.
Autoimmun Rev ; 18(4): 325-333, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30825520

RESUMO

BACKGROUND: Myositis is a heterogeneous group of muscular auto-immune diseases with clinical and pathological criteria that allow the classification of patients into different sub-groups. Inclusion body myositis is the most frequent myositis above fifty years of age. Diagnosing inclusion body myositis requires expertise and is challenging. Little is known concerning the pathogenic mechanisms of this disease in which conventional suppressive-immune therapies are inefficacious. OBJECTIVES: Our aim was to deepen our understanding of the immune mechanisms involved in inclusion body myositis and identify specific biomarkers. METHODS: Using a panel of thirty-six markers and mass cytometry, we performed deep immune profiling of peripheral blood cells from inclusion body myositis patients and healthy donors, divided into two cohorts: test and validation cohorts. Potential biomarkers were compared to myositis controls (anti-Jo1-, anti-3-hydroxyl-3-methylglutaryl CoA reductase-, and anti-signal recognition particle-positive patients). RESULTS: Unsupervised analyses revealed substantial changes only within CD8+ cells. We observed an increase in the frequency of CD8+ cells that expressed high levels of T-bet, and containing mainly both effector and terminally differentiated memory cells. The senescent marker CD57 was overexpressed in CD8+T-bet+ cells of inclusion body myositis patients. As expected, senescent CD8+T-bet+ CD57+ cells of both patients and healthy donors were CD28nullCD27nullCD127null. Surprisingly, non-senescent CD8+T-bet+ CD57- cells in inclusion body myositis patients expressed lower levels of CD28, CD27, and CD127, and expressed higher levels of CD38 and HLA-DR compared to healthy donors. Using classification and regression trees alongside receiver operating characteristics curves, we identified and validated a frequency of CD8+T-bet+ cells >51.5% as a diagnostic biomarker specific to inclusion body myositis, compared to myositis control patients, with a sensitivity of 94.4%, a specificity of 88.5%, and an area under the curve of 0.97. CONCLUSION: Using a panel of thirty-six markers by mass cytometry, we identify an activated cell population (CD8+T-bet+ CD57- CD28lowCD27lowCD127low CD38+ HLA-DR+) which could play a role in the physiopathology of inclusion body myositis, and identify CD8+T-bet+ cells as a predominant biomarker of this disease.


Assuntos
Biomarcadores , Linfócitos T CD8-Positivos/fisiologia , Miosite de Corpos de Inclusão/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Humanos , Pessoa de Meia-Idade , Miosite de Corpos de Inclusão/imunologia , Proteínas com Domínio T/metabolismo
16.
Cell Biol Int ; 43(11): 1286-1295, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30912221

RESUMO

Telocytes had been identified as a peculiar stromal cell type implicated in tissue homeostasis and the development and pathophysiology of diseases. Telocyte existed in most organs and tissues in humans and animals. However, few studies have examined telocytes in ApoE gene deficient mice. In our studies, we verified the existence, the morphology and immunohistochemical characteristics of telocytes in critical organs of the ApoE-/- mice. Male adult ApoE-/- mice were selected as an experimental model. Immunohistochemical bio-markers, such as CD34, CD117, CD28, Vimentin and PDGFR-α were utilized to determine the distribution and morphology of telocytes in the heart, liver and kidney. Telocyte expressed positively for CD34 and CD117, and partial telocyte and telopode expressed positively for PDGFR-α in heart and liver, but negatively in kidney. Double immunofluorescence assays for CD28/Vimentin, CD34/CD117 and CD34/PDGFR-α were used to demonstrate the biochemistry speciality of telocytes, respectively. The evidence of telocytes in the ApoE-/- mice is the first step of our sturdy, which aims to demonstrate changes in telocytes in atherosclerosis in this animal model.


Assuntos
Biomarcadores/metabolismo , Rim/citologia , Fígado/citologia , Miocárdio/citologia , Telócitos/citologia , Animais , Antígenos CD34/metabolismo , Antígenos CD28/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos Knockout para ApoE , Miocárdio/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Telócitos/metabolismo , Vimentina/metabolismo
17.
Hum Immunol ; 80(9): 748-754, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30853362

RESUMO

End-stage renal disease (ESRD) patients, including those on hemodialysis, possess a high risk for cardiovascular diseases, as the first leading cause of death among them. Traditional risk factors do not utterly elucidate this. Throughout the last two decades, CD4+CD28null T cells; an unusual subset of T lymphocytes, was detected high with excess cardiovascular (CV) mortality. We aimed to investigate the circulating CD4+CD28null T cells frequency in ESRD patients on hemodialysis and to evaluate their relationship with atherosclerotic changes. High-resolution carotid ultrasonography was done to assess the common carotid artery intima media thickness in a number of ESRD patients, accordingly patients were selected and subdivided into two groups; 30 with atherosclerosis (mean [SD] age, 51.6 [6.3] years) and 30 without (mean [SD] age, 48.9 [5.5] years). Another 30 healthy individuals (mean [SD] age, 48.5 [6.8] years) were enrolled. Analysis of CD4+CD28null T-cells frequency by flow-cytometry was performed in all studied subjects. CD4+CD28null T cell percentage was significantly higher in ESRD patients, (mean [SD], 7.3 [2.7] %) compared to healthy individuals (mean [SD], 3.0 [0.8] %), (p < 0.001). Additionally, the expansion of these unusual T lymphocytes was significantly higher in ESRD patients with atherosclerotic changes (mean [SD], 9.47 [0.75] %) compared to those without atherosclerosis (mean [SD], 5.22 [2.14] %), (p < 0.001). In conclusion circulating CD4+CD28null T lymphocyte population showed expansion in ESRD patients, and of interest in correlation to preclinical atherosclerotic changes.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Falência Renal Crônica/complicações , Linfócitos Nulos/metabolismo , Diálise Renal , Adulto , Área Sob a Curva , Aterosclerose/patologia , Proteína C-Reativa/análise , Espessura Intima-Media Carotídea , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Feminino , Citometria de Fluxo , Humanos , Imunossenescência/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC
18.
Mucosal Immunol ; 12(1): 212-222, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315241

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T-cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8+ CD28null T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3+ T cells isolated from IPF lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant-derived T cells (enriched with CD28null T cells), but not normal donor lung CD28+ T cells induced dexamethasone-resistant lung remodeling in humanized NSG mice. Finally, CD28null T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28+ T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment-accelerated lung fibrosis. Together, these results demonstrate that IPF CD28null T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Pulmão/patologia , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia , Remodelação das Vias Aéreas , Animais , Anticorpos Monoclonais/metabolismo , Antígenos CD28/metabolismo , Antígeno CTLA-4/imunologia , Separação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Imunofenotipagem , Camundongos , Camundongos SCID , Receptor de Morte Celular Programada 1/imunologia
19.
Gene ; 688: 84-92, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30529248

RESUMO

Cluster of differentiation 28 (CD28) is a co-stimulatory receptor found on the surface of T cells. Takifugu obscurus is a kind of anadromous fish species. In this study, the full-length sequence of To-CD28 was obtained, including a 672-bp open reading frame that encodes a peptide chain of 223 amino acids. The phylogenetic analysis showed that To-CD28 is similar to the CD28 protein in Takifugu rubripes. The total hematocyte count distinctly decreased after TBT-Cl exposure, showing the adverse effects of TBT-Cl invasion and self-adjusting ability upon To-CD28 accumulation. The production of reactive oxygen species increased, demonstrating the oxidation resistance of T. obscurus when exposed to TBT-Cl. The tissue expression patterns indicated To-CD28 is a widely distributed receptor in T. obscurus. Its high expression in the liver and gill suggests that To-CD28 could be potentially functioned in TBT-Cl toxic process. The mRNA levels of To-CD28 and relative genes in the TLR-MyD88 signal pathway were significantly up-regulated under TBT-Cl exposure. The immunohistochemistry also showed that the To-CD28 protein signal was enhanced under TBT-Cl exposure, which proved that the positive protection of To-CD28 for maintaining homeostasis. Our study indicated that To-CD28 might participate in the toxicity mechanism upon TBT-Cl exposure and regulate homeostasis stability of T. obscurus.


Assuntos
Antígenos CD28/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Takifugu/metabolismo , Compostos de Trialquitina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Brânquias/metabolismo , Homeostase/efeitos dos fármacos , Filogenia , RNA Mensageiro/metabolismo , Rios , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos
20.
Cancer Sci ; 110(2): 530-539, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548441

RESUMO

B7-H5 and its cognate receptor CD28H are T lymphocyte second signaling transduction molecules. Here we aimed to explore the function of this pathway in pancreatic cancer in vitro and in vivo, and evaluated the clinical significance in 136 patients with pancreatic ductal adenocarcinoma enrolled from January 2012 to February 2017 in our hospital. Surgical tumor specimens were collected for immunohistochemical staining to evaluate B7-H5 expression. Patients' baseline characteristics, including gender, age, tumor size, tumor location, tumor grading, clinical TNM staging, tumor infiltrating lymphocytes, CA19-9 and chemotherapy treatment, along with the subsequent follow-up data, were documented and analyzed. When co-cultured with T cells, pancreatic cancer PC cells with high B7-H5 expression induced a more potent immune reaction, indicated by elevated cytokine release and increased proliferation of T lymphocytes compared with cells exhibiting low B7-H5 expression. Xenograft pancreatic tumors derived from high B7-H5 expression PC cells exhibited attenuated growth compared to tumors from low B7-H5 expression cells after transfusion with T lymphocytes in immune-deficient mice. Of the 136 PDAC tumor tissues, 93 (68.38%) were strong and 43 (31.62%) were weak B7-H5 expression. Patients with strong B7-H5 expression had significantly longer overall survival than those with weak expression (median: 16.5 vs 11.5 months, P = .017). TNM staging, tumor location and subsequent chemotherapy were also prognostic factors in these patients. Collectively, B7-H5/CD28H is a co-stimulatory signal pathway, and expression of B7-H5 is associated with improved disease prognosis in patients with pancreatic cancer.


Assuntos
Adenocarcinoma/metabolismo , Antígenos B7/metabolismo , Antígenos CD28/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transdução de Sinais/fisiologia , Adenocarcinoma/patologia , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Linfócitos T/metabolismo , Linfócitos T/patologia
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