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1.
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
2.
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
3.
Adv Exp Med Biol ; 1189: 53-84, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758531

RESUMO

Costimulatory signals initiated by the interaction between the tumor necrosis factor (TNF) ligand and cognate TNF receptor (TNFR) superfamilies promote clonal expansion, differentiation, and survival of antigen-primed CD4+ and CD8+ T cells and have a pivotal role in T-cell-mediated adaptive immunity and diseases. Accumulating evidence in recent years indicates that costimulatory signals via the subset of the TNFR superfamily molecules, OX40 (TNFRSF4), 4-1BB (TNFRSF9), CD27, DR3 (TNFRSF25), CD30 (TNFRSF8), GITR (TNFRSF18), TNFR2 (TNFRSF1B), and HVEM (TNFRSF14), which are constitutive or inducible on T cells, play important roles in protective immunity, inflammatory and autoimmune diseases, and tumor immunotherapy. In this chapter, we will summarize the findings of recent studies on these TNFR family of co-signaling molecules regarding their function at various stages of the T-cell response in the context of infection, inflammation, and cancer. We will also discuss how these TNFR co-signals are critical for immune regulation and have therapeutic potential for the treatment of T-cell-mediated diseases.


Assuntos
Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Imunoterapia , Ativação Linfocitária , Neoplasias
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: 153-177, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758534

RESUMO

CD4+ T cells play a central role in orchestrating the immune response to a variety of pathogens but also regulate autoimmune responses, asthma, allergic responses, as well as tumor immunity. To cover this broad spectrum of responses, naïve CD4+ T cells differentiate into one of several lineages of T helper cells, including Th1, Th2, Th17, and TFH, as defined by their cytokine pattern and function. The fate decision of T helper cell differentiation integrates signals delivered through the T cell receptor, cytokine receptors, and the pattern of co-stimulatory signals received. In this review, we summarize the contribution of co-stimulatory and co-inhibitory receptors to the differentiation and maintenance of T helper cell responses.


Assuntos
Diferenciação Celular , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Citocinas , Humanos , Transdução de Sinais , Células Th1 , Células Th17 , Células Th2
7.
Adv Exp Med Biol ; 1189: 267-312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758538

RESUMO

T cells play a pivotal role in orchestrating immune responses directed against a foreign (allogeneic) graft. For T cells to become fully activated, the T-cell receptor (TCR) must interact with the major histocompatibility complex (MHC) plus peptide complex on antigen-presenting cells (APCs), followed by a second "positive" costimulatory signal. In the absence of this second signal, T cells become anergic or undergo deletion. By blocking positive costimulatory signaling, T-cell allo-responses can be aborted, thus preventing graft rejection and promoting long-term allograft survival and possibly tolerance (Alegre ML, Najafian N, Curr Mol Med 6:843-857, 2006; Li XC, Rothstein DM, Sayegh MH, Immunol Rev 229:271-293, 2009). In addition, costimulatory molecules can provide negative "coinhibitory" signals that inhibit T-cell activation and terminate immune responses; strategies to promote these pathways can also lead to graft tolerance (Boenisch O, Sayegh MH, Najafian N, Curr Opin Organ Transplant 13:373-378, 2008). However, T-cell costimulation involves an incredibly complex array of interactions that may act simultaneously or at different times in the immune response and whose relative importance varies depending on the different T-cell subsets and activation status. In transplantation, the presence of foreign alloantigen incites not only destructive T effector cells but also protective regulatory T cells, the balance of which ultimately determines the fate of the allograft (Lechler RI, Garden OA, Turka LA, Nat Rev Immunol 3:147-158, 2003). Since the processes of alloantigen-specific rejection and regulation both require activation of T cells, costimulatory interactions may have opposing or synergistic roles depending on the cell being targeted. Such complexities present both challenges and opportunities in targeting T-cell costimulatory pathways for therapeutic purposes. In this chapter, we summarize our current knowledge of the various costimulatory pathways in transplantation and review the current state and challenges of harnessing these pathways to promote graft tolerance (summarized in Table 10.1).


Assuntos
Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Tolerância ao Transplante , Rejeição de Enxerto , Humanos , Transplante Homólogo
8.
Anticancer Res ; 39(11): 5911-5918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704815

RESUMO

BACKGROUND/AIM: Double-negative T (DNT) cells are phenotypically CD3+CD4-CD8-T cells. This study aimed to investigate the anti-cancer activity of DNT cells against pancreatic cancer cells. MATERIALS AND METHODS: DNT cells were isolated from human peripheral blood. The effect of DNT cells on proliferation and invasion of the human pancreatic cell line Panc-1 was assessed. Expression of Nrf2 and Fas in Panc-1 cells co-cultured with DNT cells was analyzed with RT-PCR. The supernatants of Panc-1 and DNT co-cultures were analyzed with ELISA for IFN-r and FasL levels. RESULTS: The isolated DNT cell phenotype was CD4-CD8-CD56- CD3+TCR (T cell receptor) α/ß+ T cells with more than 90% purity. Panc-1 cell proliferation was significantly inhibited by co-culture with DNT cells. Panc-1 cells co-cultured with DNT cells showed significantly reduced cell invasion. Panc-1 cells co-cultured with DNT cells showed increased Nrf2 and Fas mRNA expression. Increased INF-r and FasL levels were detected in the supernatants of co-cultures of DNT and pancreatic cells. CONCLUSION: DNT cells inhibited proliferation and invasion of human pancreatic cancer cells. The INF-r, Fas/FasL pathway and Nrf2 may be involved in the anti-cancer effect of DNT cells against human pancreatic cancer.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura/métodos , Ativação Linfocitária/imunologia , Neoplasias Pancreáticas/prevenção & controle , Apoptose , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Proteína Ligante Fas/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Interferon/metabolismo , Células Tumorais Cultivadas , Receptor fas/metabolismo
9.
Cancer Immunol Immunother ; 68(12): 2055-2066, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724091

RESUMO

Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4+CD25+Foxp3+ Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8+ T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Imunoterapia/métodos , Neoplasias Hepáticas/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Citotoxicidade Imunológica , Feminino , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Adulto Jovem
10.
Cancer Immunol Immunother ; 68(11): 1747-1757, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602489

RESUMO

BACKGROUND: Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. METHODS: TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. RESULTS: Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2-3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted tumor recognition. CONCLUSIONS: These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiorradioterapia , Cistadenocarcinoma Seroso/terapia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Terapia de Salvação , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/secundário , Citotoxicidade Imunológica/imunologia , Feminino , Seguimentos , Humanos , Ativação Linfocitária , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Prognóstico
11.
Nature ; 574(7777): 200-205, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31582858

RESUMO

The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Vírus da Hepatite B/imunologia , Hepatócitos/imunologia , Hepatócitos/virologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Feminino , Hepatite B/tratamento farmacológico , Hepatite B/imunologia , Hepatite B/virologia , Humanos , Tolerância Imunológica , Interleucina-2/imunologia , Interleucina-2/uso terapêutico , Macrófagos do Fígado/imunologia , Ativação Linfocitária , Masculino , Camundongos , Transcriptoma/genética
12.
Mol Biol (Mosk) ; 53(5): 838-848, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661482

RESUMO

Lymphocyte phosphatase-associated phosphoprotein (LPAP) is a small transmembrane protein that is found in lymphocytes and is tightly associated with the phosphatase CD45. The function of LPAP is still unknown. Studies of the LPAP interactome may reveal new details of how C45 and lymphocyte signaling in general are regulated. LPAP binding partners were sought using coimmunoprecipitation coupled with mass spectrometry, stabilization of protein complexes with chemical crosslinkers, and Blue Native electrophoresis. In addition to CD45, several proteins were identified as LPAP partners, including CD71, CD98, cytoskeletal proteins, the amino acid transporter SLC1A4, and the cell signaling component HS1. It was confirmed that more than 70% of LPAP molecules were bound with CD45 in a 1 : 1 complex. The effect of CD45 on LPAP was studied in CEM and Jurkat cells with a CD45 knockout. The LPAP levels in the cells were 10% of the level in wild-type cells. In the absence of CD45, LPAP phosphorylation at Ser-153 and Ser-163 was not affected, whereas phosphorylation at Ser-99 and Ser-172 decreased significantly. Based on the results, CD45 was assumed to play a role in regulating LPAP expression and phosphorylation status.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Mapas de Interação de Proteínas , Sistema ASC de Transporte de Aminoácidos/metabolismo , Antígenos CD/metabolismo , Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Antígenos Comuns de Leucócito/metabolismo , Proteínas de Membrana/química , Fosforilação , Ligação Proteica , Receptores da Transferrina/metabolismo
13.
Cancer Immunol Immunother ; 68(10): 1635-1648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549214

RESUMO

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 µg) or PAS (100 and 250 µg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral , Vacinação , Animais , Linhagem Celular Tumoral , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/imunologia
14.
Cancer Immunol Immunother ; 68(10): 1649-1660, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31562536

RESUMO

It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes significantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specific protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lymphocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition significantly augmented the number of tumor-infiltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy.


Assuntos
Pontos de Checagem do Ciclo Celular , Ativação Linfocitária , Neoplasias Ovarianas/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 3/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Feminino , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína-Tirosina Quinase ZAP-70/metabolismo
15.
Int J Nanomedicine ; 14: 6601-6613, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496701

RESUMO

Purpose: The primary goal of the present study was to explore and evaluate the highly conserved Neisserial surface protein A (NspA) molecule, fused with truncated HBV virus-like particles (VLPs), as a candidate vaccine against the virulent Neisseria meningitidis serogroup B (NMB). Methods: NspA was inserted into the major immunodominant region of the truncated hepatitis B virus core protein (HBc; amino acids 1-144). The chimeric protein, HBc-N144-NspA, was expressed from a prokaryotic vector and generated HBc-like particles, as determined by transmission electron microscopy. Further, the chimeric protein and control proteins were used to immunize mice and the resulting immune responses evaluated by flow cytometry, enzyme-linked immunosorbent assay, and analysis of serum bactericidal activity (SBA) titer. Results: Evaluation of the immunogenicity of the recombinant HBc-N144-NspA protein showed that it elicited the production of high levels of NspA-specific total IgG. The SBA titer of HBc-N144-NspA/F reached 1:16 2 weeks after the last immunization in BALB/c mice, when human serum complement was included in the vaccine. Immunization of HBc-N144-NspA, even without adjuvant, induced high levels of IL-4 and a high IgG1 to IgG2a ratio, confirming induction of an intense Th2 immune response. Levels of IL-17A increased rapidly in mice after the first immunization with HBc-N144-NspA, indicating the potential for this vaccine to induce a mucosal immune response. Meanwhile, the immunization of HBc-N144-NspA without adjuvant induced only mild inflammatory infiltration into the mouse muscle tissue. Conclusion: This study demonstrates that modification using HBc renders NspA a candidate vaccine, which can trigger protective immunity against NMB.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Vírus da Hepatite B/metabolismo , Infecções Meningocócicas/imunologia , Infecções Meningocócicas/prevenção & controle , Neisseria meningitidis/patogenicidade , Sorogrupo , Vírion/metabolismo , Adjuvantes Imunológicos/farmacologia , Sequência de Aminoácidos , Animais , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/ultraestrutura , Citocinas/metabolismo , Escherichia coli/metabolismo , Feminino , Imunidade , Imunização , Inflamação/patologia , Ativação Linfocitária/imunologia , Infecções Meningocócicas/patologia , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/imunologia , Teste Bactericida do Soro , Baço/microbiologia , Linfócitos T/imunologia , Vacinação , Virulência
16.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
17.
Cancer Sci ; 110(11): 3415-3423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513320

RESUMO

Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy, which is one of the most promising cancer therapies, is licensed for treating various tumors. Programmed death-ligand 1, which is expressed on the surface of cancer cells, leads to the inhibition of T lymphocyte activation and immune evasion if it binds to the receptor PD-1 on CTLs. Anti-PD-1/PD-L1 Abs inhibit interactions between PD-1 and PD-L1 to restore antitumor immunity. Although certain patients achieve effective responses to anti-PD-1/PD-L1 therapy, the efficacy of treatment is highly variable. Clinical trials of anti-PD-1/PD-L1 therapy combined with radiotherapy/chemotherapy are underway with suggestive evidence of favorable outcome; however, the molecular mechanism is largely unknown. Among several molecular targets that can influence the efficacy of anti-PD-1/PD-L1 therapy, PD-L1 expression in tumors is considered to be a critical biomarker because there is a positive correlation between the efficacy of combined treatment protocols and PD-L1 expression levels. Therefore, understanding the mechanisms underlying the regulation of PD-L1 expression in cancer cells, particularly the mechanism of PD-L1 expression following DNA damage, is important. In this review, we consider recent findings on the regulation of PD-L1 expression in response to DNA damage signaling in cancer cells.


Assuntos
Antígeno B7-H1/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Neoplasias/metabolismo , Medicina de Precisão , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Comunicação Celular , Pontos de Checagem do Ciclo Celular , Morte Celular/fisiologia , Dano ao DNA , Fragmentação do DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , Humanos , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Instabilidade de Microssatélites , Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Nucleotidiltransferases/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Mensageiro/metabolismo , Evasão Tumoral , Regulação para Cima
18.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31543394

RESUMO

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Assuntos
Arterite de Células Gigantes/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/patologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiologia , Interleucinas/biossíntese , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/fisiopatologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia
19.
DNA Cell Biol ; 38(11): 1402-1410, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31556705

RESUMO

Tumor antigen-induced lymphocyte transformation (LT) represents the antitumor cellular immunity, which might correlate with the cancer treatment outcome. Currently, there is no LT assay (LTA) routinely used in clinic. To establish a sensitive and convenient procedure for LTA, the same samples were used to simultaneously perform three assays: 5-ethynyl-2'-deoxyuridine (EdU) assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and carboxyfluorescein succinimidyl ester (CFSE) assay, and then the three results were compared. Several conditions were optimized: the LT harvest time, sources of lymphocytes (blood, lymph nodes, or spleen), the added amount of stimulatory tumor antigen and in vivo immunization priming time for LTA. The results of side-by-side comparison showed that (1) the 72 h for coculture of lymphocytes with tumor antigens was optimal time to harvest cells for LTA; (2) 50 µg/mL of tumor antigens was the optimal concentration for activation LT from three sources; (3) EdU incorporation was the sensitive and convenient assay for LTA as compared with MTT and CFSE assays; (4) the day 21-28 after in vivo priming immunization was the testing time for LTA; and (5) peripheral blood LT could be a good representative of whole body's lymphocyte reaction and practically easy cell source for LTA. This comparison of the three LTA in mouse model suggests that the EdU incorporation assay might be useful to evaluate the antitumor immunity stimulated by specific tumor vaccine or different anticancer therapies.


Assuntos
Antígenos de Neoplasias/imunologia , Bioensaio/métodos , Ativação Linfocitária/fisiologia , Linfócitos/fisiologia , Animais , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Células Cultivadas , Técnicas de Cocultura , Monitoramento de Medicamentos/métodos , Feminino , Corantes Fluorescentes/análise , Corantes Fluorescentes/metabolismo , Humanos , Imunidade Celular/fisiologia , Imunoensaio/métodos , Camundongos , Camundongos Endogâmicos ICR
20.
Int J Infect Dis ; 86: 178-187, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398453

RESUMO

OBJECTIVES: Most previous studies on poor immunological responders (PIRs) have been performed on one cohort at one time-point following highly active antiretroviral therapy (HAART). The aim of this study was to investigate whether there are different subtypes of PIR and whether a certain population might achieve better immune reconstitution following longer HAART. METHODS: This study was designed as an ambispective cohort study, including a 4-5-year retrospective study and a 2-year prospective follow-up investigation. Thymic output, activated T cell and regulatory T cell (Treg) subset frequencies, expression levels of interferon-stimulated genes, and plasma concentrations of neopterin were determined at 4-5 years and 6-7 years following HAART initiation. RESULTS: PIRs were subdivided into two populations after 4-5 years of HAART, according to the kinetics of T cell recovery. Type II PIRs exhibited a significantly lower percentage of naïve CD4+ T cells and CD31+ naïve CD4+ T cells compared with type I PIRs. After an additional 2 years of HAART treatment, type I PIRs showed a better outcome than type II PIRs. Furthermore, it was found that 2 years of additional HAART could persistently improve thymic output. CONCLUSIONS: The two PIR subgroups are different in terms of immune characteristics and the response to prolonged HAART.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Esquema de Medicação , Feminino , Seguimentos , HIV-1/imunologia , Humanos , Ativação Linfocitária , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Linfócitos T Reguladores/imunologia , Carga Viral
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