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1.
Eur J Immunol ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31465113

RESUMO

Icaritin, a hydrolytic product of icariin isolated from traditional Chinese herbal medicine genus Epimedium, has many pharmacological and biological activities. Here, we show that icaritin can effectively decrease tumor burden of murine B16F10 melanoma and MC38 colorectal tumors in a T cell-dependent manner. The treatment effects are associated with increased CD8 T cell infiltration and increased effector memory T cell frequency. In vivo depletion of CD8 T cell using an anti-CD8 monoclonal antibody abolished the antitumor effect, which supports the critical role of CD8 T cells during icaritin treatment. By analyzing immune cells in the tumor tissue, we found reduced frequency of CD11b+ Gr1+ myeloid-derived suppression cells (MDSCs) infiltration and downregulation of PD-L1 expression on MDSCs after icaritin treatment. This was not limited to MDSCs, as icaritin also decreased the expression of PD-L1 on neutrophils. Importantly, the combination of anti-PD-1/CTLA-4 and icaritin significantly enhances antitumor ability and increases the efficacy of either treatment alone. Our findings reveal that icaritin induces antitumor immunity in a CD8 T cell-dependent way and justify further investigation of combining immune checkpoint therapy to icaritin-based antitumor therapy. This article is protected by copyright. All rights reserved.

2.
Mol Genet Genomic Med ; : e919, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407515

RESUMO

BACKGROUND: Left cardiac pumping function determines the compensatory capacity of the cardiovascular system following acute high-altitude exposure. Variations in cardiac output (CO) at high altitude are inconsistent between individuals, and genetic susceptibility may play a crucial role. We sought to identify genetic causes of cardiac pumping function variations and describe the genotype-phenotype correlations. METHODS: A total of 151 young male volunteers were recruited and transferred to Lhasa (3,700 m) from Chengdu (<500 m) by plane. Genetic information related to hypoxic signaling and cardiovascular-related pathways was collected before departure. Echocardiography was performed both before departure and 24 hr after arrival at high altitude. RESULTS: Here we reported that PPARA variants were closely related to high-altitude cardiac function. The variants of rs6520015 C-allele and rs7292407 A-allele significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure. In addition, the individuals carrying haplotypes in PPARA, namely, rs135538 C-allele, rs4253623 A-allele, rs6520015 C-allele and rs7292407 A-allele (C-A-C-A), suffered a 7.27-fold risk for cardiac pumping function reduction (95% CI: 2.39-22.15, p = .0006) compared with those carrying the wild-type haplotype. CONCLUSIONS: This self-controlled study revealed that PPARA variations significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure, providing a potential predictive marker before high-altitude exposure and targets in mechanistic studies.

3.
J Immunol ; 203(2): 323-327, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175159

RESUMO

The differentiation of memory CD8+ T cells is critical to the long-term cellular immunity. The transcription factor BCL6 has been reportedly important for the generation and maintenance of memory CD8+ T cells; however, using the newly established BCL6 conditional knockout mouse model, we demonstrate that BCL6 is dispensable for the maintenance of established memory CD8+ T cell pool, although BCL6 is still required for the generation of CD8+ memory precursors upon acute viral infection. In addition, BCL6 promotes the expression of TCF-1 via directly binding to the Tcf7 (gene symbol for TCF-1) allele in CD8+ memory precursors and forced expression of TCF-1 restores the generation of BCL6-deficient memory precursors. Thus, our findings clarify that BCL6 is dispensable for the maintenance of memory CD8+ T cells, but functions as an important upstream of TCF-1 to regulate the generation of memory precursors in acute viral infection.

4.
Nat Commun ; 10(1): 1507, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944315

RESUMO

Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Células Matadoras Naturais/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Hepatite C Crônica/virologia , Hepatócitos/virologia , Antígenos de Histocompatibilidade Classe I/imunologia , Interferon gama/imunologia , Ativação Linfocitária/fisiologia , Proteínas de Membrana/imunologia , Camundongos , Distribuição Aleatória
5.
Biomater Sci ; 7(6): 2533-2544, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30968875

RESUMO

Cytotoxic CD8+ T cells (CTLs) are crucial for controlling intracellular pathogens as well as cancer. However, how to promote the cytotoxic activity of CTL cells in vitro and in vivo remains largely unknown. On the other hand, ceria nanoparticles (CNPs) are widely used in biomedical fields, but the role of CNPs in CTL cells is still unclear. In this study, we found that the activated antigen-specific (P14) and nonspecific CD8+ T cells with CNP treatment both produced more cytokines, including interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α), and released more effector molecules, such as granzyme B and perforin, and then exhibited higher killing activity of P14 cells in vitro and stronger viral clearance capacity of CTL cells in vivo. Mechanistically, the activated P14 cells with CNP treatment inhibited the production of reactive oxygen species, and therefore promoted the activity of NF-κB signaling. Importantly, while the P14 cells were simultaneously treated by IMD-0354, a specific inhibitor of NF-κB signaling, the increases of IL-2 and TNF-α productions and granzyme B and perforin releases were remedied, and the P14 cells eventually exhibited the natural killing activity in vitro. Thus, our results demonstrated that CNP treatment promoted the cytotoxic activity of CTL cells and provide new ideas in the usage of CNPs and fascinating pharmacological potentials for clinical application, especially cancer immunotherapy.

6.
Front Immunol ; 10: 606, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984183

RESUMO

Follicular helper T cells (TFH cells), known as the primary "helpers" of the germinal center (GC) reaction, promote the humoral immune response to defend against various pathogens. Under conditions of infection by different types of pathogens, many shared transcription factors (TFs), such as Bcl-6, TCF-1, and Maf, are selectively enriched in pathogen-specific TFH cells, orchestrating TFH cell differentiation and function. In addition, TFH cells also coexpress environmentally associated TFs as their conventional T cell counterparts (such as T-bet, GATA-3, or ROR-γt, which are expressed in Th1, Th2, or Th17 cells, respectively). These features likely indicate both the lineage-specificity and environmental adaption of the TFH cell responses. However, the extent to which the TFH cell response relies on these environmentally specific TFs is not completely understood. Here, we found that T-bet was specifically expressed in Type I TFH cells but not Type II TFH cells. While dispensable for the early fate commitment of TFH cells, T-bet was essential for the maintenance of differentiated TFH cells, promoting their proliferation, and inhibiting their apoptosis during acute viral infection. Microarray analysis showed both similarities and differences in transcriptome dependency on T-bet in TFH and TH1 cells, suggesting the distinctive role of T-bet in TFH cells. Collectively, our findings reveal an important and specific supporting role for T-bet in type I TFH cell response, which can help us gain a deeper understanding of TFH cell subsets.

7.
Cell Mol Immunol ; 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842630

RESUMO

Epigenetic modifications to histones dictate the differentiation of naïve CD4+ T cells into different subsets of effector T helper (TH) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of TH1, TH2 and regulatory T (Treg) cells. However, whether and how EZH2 regulates follicular helper T (TFH) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells. Ablation of EZH2 in LCMV-specific CD4+ T cells leads to a selective impairment of early TFH cell fate commitment, but not late TFH differentiation or memory TFH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs TFH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.

8.
Front Immunol ; 10: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814995

RESUMO

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.

9.
Immunity ; 50(2): 403-417.e4, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709740

RESUMO

The tolerogenic microenvironment of the liver is associated with impaired hepatic T cell function. Here, we examined the contribution of liver-resident natural killer (LrNK) cells, a prominent hepatic NK cell compartment, to T cell antiviral responses in the liver. The number of virus-specific T cells increased in LrNK-cell-deficient mice during both acute and chronic lymphocytic choriomeningitis virus infection. Upon infection with adenovirus, hepatic T cells from these mice produced more cytokines, which was accompanied by reduced viral loads. Transfer of LrNK cells into LrNK-cell-deficient or wild-type mice inhibited hepatic T cell function, resulting in impaired viral clearance, whereas transfer of conventional NK cells promoted T cell antiviral responses. LrNK-cell-mediated inhibition of T cell function was dependent on the PD-1-PD-L1 axis. Our findings reveal a role for LrNK cells in the regulation of T cell immunity and provide insight into the mechanisms of immune tolerance in the liver.


Assuntos
Antígeno B7-H1/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Células Matadoras Naturais/metabolismo , Fígado/metabolismo , Fígado/virologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Transcriptoma/genética , Transcriptoma/imunologia
10.
Sci Adv ; 5(1): eaau7426, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30662948

RESUMO

Hyperactivation of the NLRP3 inflammasome contributes to the pathogenesis of multiple diseases, but the mechanisms underlying transcriptional regulation of Nlrp3 remain elusive. We demonstrate here that macrophages lacking V-set and immunoglobulin domain-containing 4 (Vsig4) exhibit significant increases in Nlrp3 and Il-1ß transcription, caspase-1 activation, pyroptosis, and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimuli. VSIG4 interacts with MS4A6D in the formation of a surface signaling complex. VSIG4 occupancy triggers Ser232 and Ser235 phosphorylation in MS4A6D, leading to activation of JAK2-STAT3-A20 cascades that further results in nuclear factor κB suppression and Nlrp3 and Il-1ß repression. Exaggerated NLRP3 and IL-1ß expression in Vsig4-/- mice is accountable for deleterious disease severity in experimental autoimmune encephalomyelitis (EAE) and resistance to dextran sulfate sodium (DSS)-induced colitis. The agonistic VSIG4 antibodies (VG11), acting through NLRP3 and IL-1ß suppression, show significant therapeutic efficacy in mouse EAE. These findings highlight VSIG4 as a prospective target for treating NLRP3-associated inflammatory disorders.

11.
Clin Epigenetics ; 10(1): 149, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497529

RESUMO

Multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system, is characterized by axonal degeneration and gliosis. Although the causes of MS remain unknown, gene dysregulation in the central nervous system has been associated with the disease pathogenesis. As such, the various regulators of gene expression may be contributing factors. The noncoding (nc) RNAs have piqued the interest of MS researchers due to their known functions in human physiology and various pathological processes, despite being generally characterized as transcripts without apparent protein-coding capacity. Accumulating evidence has indicated that ncRNAs participate in the regulation of MS by acting as epigenetic factors, especially the long (l) ncRNAs and the micro (mi) RNAs, and they are now recognized as key regulatory molecules in MS. In this review, we summarize the most current studies on the contribution of ncRNAs in MS pathogenic processes and discuss their potential applications in the diagnosis and treatment of MS.

12.
ACS Nano ; 12(11): 11579-11590, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30265798

RESUMO

While there has been extensive development of soluble epitope-specific peptides to induce immune tolerance for the treatment of autoimmune diseases, the clinical efficacy of soluble-peptides-based immunotherapy was still uncertain. Recent strategies to develop antigen carriers coupled with peptides have shown promising results in preclinical animal models. Here we developed functional amphiphilic hyperbranched (HB) polymers with different grafting degrees of hydrophobic chains as antigen myelin antigen oligodendrocyte glycoprotein (MOG) peptide carriers and evaluated their ability to induce immune tolerance. We show that these polymers could efficiently deliver antigen peptide, and the uptake amount by bone marrow dendritic cells (BMDCs) was correlated with the hydrophobicity of polymers. We observe that these polymers have a higher ability to activate BMDCs and a higher efficacy to induce antigen-specific T cell apoptosis than soluble peptides, irrespective of hydrophobicity. We show that intravenous injection of polymer-conjugated MOG peptide, but not soluble peptide, markedly treats the clinical symptoms of experimental autoimmune encephalomyelitis in mice. Together, these results demonstrate the potential for using amphiphilic HB polymers as antigen carriers to deliver peptides for pathogenic autoreactive T cell deletion/tolerance strategies to treat autoimmune disorders.

13.
Front Immunol ; 9: 1127, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875775

RESUMO

Follicular helper CD4+ T (TFH) cells are critical for optimal B-cell-mediated humoral immunity by initiating, fueling, and sustaining germinal center reactions. The differentiation of TFH cells relies on multiple intrinsic and extrinsic factors; however, the details by which these factors are integrated to coordinate TFH differentiation are largely unknown. In this study, using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) viral infection, we demonstrate that mTOR complex 2 (mTORC2) kinase integrates TCR signaling and ICOS-mediated co-stimulation to promote late differentiation and functional maturation of virus-specific TFH cells. Specifically, mTORC2 functions to maintain TFH lineage specifications, including phenotypes, migratory characteristics, and functional properties. Thus, our results highlight the importance of mTORC2 in guarding TFH phenotypic and functional maturation.

14.
Eur J Immunol ; 48(9): 1539-1549, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29856484

RESUMO

The presence of shared T-cell clonotypes was found in several different diseases, but its relationship with the progression of disease remains unclear. By sequencing the complementary determining region 3 of T-cell receptor (TCR) ß chains from the purified antigen-experienced CD8+ T cells, we characterized the T-cell repertoire in a prospective cohort study among 75 patients with chronic hepatitis B in China, as well as a healthy control and a validation cohort. We found that most T-cell clones from patients harbored the "patient-specific" TCR sequences. However, "patient-shared" TCR clonotypes were also widely found, which correlated with the favorable turnover of disease. Interestingly, the frequency of the "patient-shared" clonotypes can serve as a biomarker for favorable prognosis. Based on the clonotypes in those patients with favorable outcomes, we created a database including several clusters of protective anti-HBV CD8+ T-cell clonotypes that might be a reasonable target for therapeutic vaccine development or adoptive cell transfer therapy. These findings were validated in an additional independent cohort of patients. These results suggest that the "patient-shared" TCR clonotypes may serve as a valuable prognostic tool in the treatment of chronic hepatitis B and possibly other chronic viral diseases.

15.
Cell Mol Immunol ; 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29955175

RESUMO

Autoreactive CD8+ T cells, which play an indispensable role in ß cell destruction, represent an emerging target for the prevention of type 1 diabetes (T1D). Altered peptide ligands (APLs) can efficiently induce antigen-specific T cells anergy, apoptosis or shifts in the immune response. Here, we found that HLA-A*0201-restricted CD8+ T cell responses against a primary ß-cell autoantigen insulin epitope InsB15-14 were present in both NOD.ß2mnull.HHD NOD mice and T1D patients. We generated several APL candidates for InsB15-14 by residue substitution at the p6 position. Only H6F exhibited an inhibitory effect on mInsB15-14-specific CD8+ T cell responses in vitro. H6F treatment significantly reduced the T1D incidence, which was accompanied by diminished autoreactive CD8+ T cell responses to mInsB15-14, inhibited infiltration of CD8+ and CD4+ T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.ß2mnull.HHD mice. Mechanistically, H6F treatment significantly augmented a tiny portion of CD8+CD25+Foxp3+ T cells in the spleen and especially in the pancreas. This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity. Therefore, this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.

16.
Front Immunol ; 9: 904, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29774026

RESUMO

Inflammatory bowel disease (IBD) is associated with dysregulation of both innate and adaptive immune response in the intestine. MicroRNA (miR)-155 is frequently expressed and functions in many immune cell types. Besides its function in adaptive immunity, miR-155 is a key regulator of the innate immune response in macrophages, dendritic cells, and even in epithelia cells. Although the roles of miR-155 within T and B lymphocytes in colitis have been reported, its function in innate immune cells has not been thoroughly examined. In this study, the dextran sulfate sodium (DSS)-induced colitis model was established in wild-type (WT) and miR-155-/- mice. Our results showed that miR-155 deficiency in macrophages recapitulated the alleviated colitis feature of miR-155-/- mice and appeared to skew toward the alterative M2 phenotype. Notably, the predominance of M2 in colon can result in dampened intestinal immune cell proliferation and inhibit CD4 T cell polarization toward Th1 and Th17. Moreover, C/EBPß and SOCS1 were demonstrated as two key functional targets in this process. We also provided evidence for use of miR-155 inhibitor to treat colitis. Collectively, the findings highlight the central role of alternative M2 skewing for miR-155 function in colitis and reveal that macrophages might be a main target for therapeutics.

17.
Pancreatology ; 18(3): 231-237, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29502986

RESUMO

Interleukin-22 (IL-22) is involved in the development of lymphocytes and serves as a rapid and early source of the effector cytokines that are released in response to pathogen-induced changes in the microenvironment. Recent research has implicated IL-22 as a potential contributing factor to the spectrum of inflammation-related pancreatic diseases, particularly pancreatitis, fibrosis, carcinoma and diabetes. In this review, we summarize the current knowledge on the roles of IL-22 in the various pancreatic pathogenesis, providing insights into the underlying cellular and signaling mechanisms that will help guide future research into promising interventional targets with therapeutic potential.


Assuntos
Interleucinas/genética , Interleucinas/metabolismo , Pancreatopatias/genética , Pancreatopatias/metabolismo , Animais , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Humanos , Transdução de Sinais/genética
18.
Biochem Biophys Res Commun ; 497(1): 153-159, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29438710

RESUMO

Due to their identical inheritance and shared surroundings, identical twins have been the recommended group for studying the susceptibility and prognosis of diseases. Here, CD8+ T cell receptor beta (TCRß) chains were analyzed by high-throughput sequencing in three pairs of healthy identical twins and chronic hepatitis B patients. The data showed a high level of similarity in the TCR repertoire of each pair in terms of average TCR Vß segment expression and frequency of the complementary determining region 3 (CDR3) pattern and skewed or oligoclonal clonotypes. Notably, the level of similarity in TCR Vß expression between the twins appeared to be independent of the consistency or inconsistency of chronic HBV infection, although the detailed CDR3 pattern and frequency were related to disease prognosis. There were more immunodominant clonotypes in patients with HBV antigen seroconversion, which showed an increased abundance. These immunodominant clonotypes may be used as favorable prognostic biomarkers and potential targets for immunotherapy. Thus, delineating the CD8+ T cell repertoire of identical twins with concordant chronic viral infections provides a promising means to screen protective TCR genes for immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/patologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Gêmeos Monozigóticos , Adolescente , Adulto , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Cancer Lett ; 412: 30-36, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29031586

RESUMO

Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stageⅠto stage Ⅳ), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression. Blockage of C5a/C5aR signaling with a C5aR antagonist reversed the C5a-induced inhibitory effect on p21/p-p21 expression. C5a administration to cells pre-treated with a PI3K inhibitor also prevented this inhibitory effect, suggesting the involvement of the PI3K/AKT signaling pathway in C5a/C5aR-mediated suppression of p21/p-p21 expression. In vivo C5aR antagonist treatment caused significant reduction in tumor growth in mice, accompanied by a remarkable elevation in p21/p-p21 expression and reduction in p-PI3K/AKT activation. These results indicate that the C5a/C5aR pathway promotes gastric cancer pathogenesis by suppressing p21/p-p21 expression via activation of PI3K/AKT signaling.


Assuntos
Complemento C5a/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Receptor da Anafilatoxina C5a/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Gástricas/etiologia , Animais , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Regulação para Baixo , Feminino , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia
20.
Cell Mol Immunol ; 15(9): 815-826, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28287115

RESUMO

CD4+ T cells are essential for sustaining CD8+ T cell responses during a chronic infection. The adoptive transfer of virus-specific CD4+ T cells has been shown to efficiently rescue exhausted CD8+ T cells. However, the question of whether endogenous virus-specific CD4+ T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8+ T cells remains unexplored. In this study, we developed a CD4+ T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We primed chronically LCMV-infected mice with a Listeria monocytogenes vector that expressed the LCMV glycoprotein-specific I-Ab-restricted CD4+ T cell epitope GP61-80 (LM-GP61) and subsequently boosted the primed mice with an influenza virus A (PR8 strain) vector that expressed the same CD4+ T cell epitope (IAV-GP61). This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4+ T cell responses, which further improved both the quantity and quality of the virus-specific CD8+ T cells and led to better control of the viral loads. The combination of this strategy and the blockade of the programmed cell death-1 (PD-1) inhibitory pathway further enhanced the anti-viral CD8+ T cell responses and viral clearance. Thus, a heterologous prime-boost immunization that selectively induces virus-specific CD4+ T cell responses in conjunction with blockade of the inhibitory pathway may represent a promising therapeutic approach to treating patients with chronic viral infections.

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