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1.
Front Immunol ; 11: 1638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695123

RESUMO

The SARS-CoV2 (COVID-19) pandemic and uncertainties in developing a vaccine have created an urgent need for new therapeutic approaches. A key question is whether it is possible to make rational predictions of new therapies based on the presently available scientific and medical information. In this regard, I have noticed an omission in the present analysis in the literature related to the exploitation of glycogen synthase kinase 3 (GSK-3) as a therapeutic approach. This is based on two key observations, that GSK-3 inhibitors can simultaneously block SARs viral replication, while boosting CD8+ adaptive T-cell and innate natural killer (NK) responses. Firstly, it is already clear that GSK-3 phosphorylation of SARs CoV1 N protein on key serine residues is needed for viral replication such that small molecule inhibitors (SMIs) of GSK-3 can inhibit viral replication. In comparing protein sequences, I show here that the key sites in the N protein of SARs CoV1 N for replication are conserved in SARs CoV2. This strongly suggests that GSK-3 SMIs will also inhibit SARs Cov2 replication. Secondly, we and others have previously documented that GSK-3 SMIs markedly enhance CD8+ cytolytic T-cell (CTL) and NK cell anti-viral effector functions leading to a reduction in both acute and chronic viral infections in mice. My hypothesis is that the repurposing of low-cost inhibitors of GSK-3 such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the virus. To date, there has been no mention of this dual connection between GSK-3 and SARs CoV2 in the literature. To my knowledge, no other drugs exist with the potential to simultaneously target both viral replication and immune response against SARs CoV2.


Assuntos
Betacoronavirus/fisiologia , Linfócitos T CD8-Positivos , Inibidores Enzimáticos/uso terapêutico , Quinase 3 da Glicogênio Sintase , Imunidade Celular/efeitos dos fármacos , Células Matadoras Naturais , Replicação Viral/efeitos dos fármacos , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Humanos , Células Matadoras Naturais/enzimologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia
2.
BMC Res Notes ; 13(1): 163, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188506

RESUMO

OBJECTIVE: The threonine/serine kinase glycogen synthase kinase 3 (GSK-3) targets multiple substrates in T-cells, regulating the expression of Tbet and PD-1 on T-cells. However, it has been unclear whether GSK-3 can affect the motility of T-cells and their interactions with antigen presenting cells. RESULTS: Here, we show that GSK-3 controls T-cell motility and interactions with other cells. Inhibition of GSK-3, using structurally distinct inhibitors, reduced T-cell motility in terms of distance and displacement. While SB415286 reduced the number of cell-cell contacts, the dwell times of cells that established contacts with other cells did not differ for T-cells treated with SB415286. Further, the increase in cytolytic T-cell (CTL) function in killing tumor targets was not affected by the inhibition of motility. This data shows that the inhibition of GSK-3 has differential effects on T-cell motility and CTL function where the negative effects on cell-cell interactions is overridden by the increased cytolytic potential of CTLs.

3.
Cell Mol Immunol ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005952

RESUMO

Modulation of T-cell responses has played a key role in treating cancers and autoimmune diseases. Therefore, understanding how different receptors on T cells impact functional outcomes is crucial. The influence of B7-H7 (HHLA2) and CD28H (TMIGD2) on T-cell activation remains controversial. Here we examined global transcriptomic changes in human T cells induced by B7-H7. Stimulation through TCR with OKT3 and B7-H7 resulted in modest fold changes in the expression of select genes; however, these fold changes were significantly lower than those induced by OKT3 and B7-1 stimulation. The transcriptional changes induced by OKT3 and B7-H7 were insufficient to provide functional stimulation as measured by evaluating T-cell proliferation and cytokine production. Interestingly, B7-H7 was coinhibitory when simultaneously combined with TCR and CD28 stimulation. This inhibitory activity was comparable to that observed with PD-L1. Finally, in physiological assays using T cells and APCs, blockade of B7-H7 enhanced T-cell activation and proliferation, demonstrating that this ligand acts as a break signal. Our work defines that the transcriptomic changes induced by B7-H7 are insufficient to support full costimulation with TCR signaling and, instead, B7-H7 inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling.

4.
Cell Rep ; 30(7): 2075-2082.e4, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32075731

RESUMO

Immune checkpoint blockade using antibodies against negative co-receptors such as cytolytic T cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has seen much success treating cancer. However, most patients are still not cured, underscoring the need for improved treatments and the possible development of small molecule inhibitors (SMIs) for improved immunotherapy. We previously showed that glycogen synthase kinase (GSK)-3α/ß is a central regulator of PD-1 expression, where GSK-3 inhibition down-regulates PD-1 and enhances CD8+ cytolytic T cell (CTL) function, reducing viral infections and tumor growth. Here, we demonstrate that GSK-3 also negatively regulates Lymphocyte Activation Gene-3 (LAG-3) expression on CD4+ and CD8+ T cells. GSK-3 SMIs are more effective than LAG-3 blockade alone in suppressing B16 melanoma growth, while their combination resulted in enhanced tumor clearance. This was linked to increased expression of the transcription factor, Tbet, which bound the LAG-3 promoter, inhibiting its transcription, and to increased granzyme B and interferon-γ1 expression. Overall, we describe a small molecule approach to inhibit LAG-3, resulting in enhanced anti-tumor immunity.

5.
Sci Immunol ; 5(43)2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31901075

RESUMO

PD-1 mediates antitumor immunity by regulating lineage fate commitment and function of myeloid cells (see related Research Article by Strauss et al..).


Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Imunoterapia , Células Mieloides
6.
J Immunol ; 203(11): 3023-3036, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31666306

RESUMO

Although the immune adaptor SH2 domain containing leukocyte phosphoprotein of 76 kDa (SLP-76) integrates and propagates the TCR signaling, the regulation of SLP-76 during the TCR signaling is incompletely studied. In this article, we report that SLP-76 interacts with the small ubiquitin-like modifier (SUMO) E2 conjugase Ubc9 and is a substrate for Ubc9-mediated SUMOylation in human and mouse T cells. TCR stimulation promotes SLP-76-Ubc9 binding, accompanied by an increase in SLP-76 SUMOylation. Ubc9 binds to the extreme C terminus of SLP-76 spanning residues 516-533 and SUMOylates SLP-76 at two conserved residues K266 and K284. In addition, SLP-76 and Ubc9 synergizes to augment the TCR-mediated IL-2 transcription by NFAT in a manner dependent of SUMOylation of SLP-76. Moreover, although not affecting the TCR proximal signaling events, the Ubc9-mediated SUMOylation of SLP-76 is required for TCR-induced assembly of Ubc9-NFAT complex for IL-2 transcription. Together, these results suggest that Ubc9 modulates the function of SLP-76 in T cell activation both by direct interaction and by SUMOylation of SLP-76 and that the Ubc9-SLP-76 module acts as a novel regulatory complex in the control of T cell activation.

7.
Nat Commun ; 10(1): 4804, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641113

RESUMO

Immunotherapy involving checkpoint blockades of inhibitory co-receptors is effective in combating cancer. Despite this, the full range of mediators that inhibit T-cell activation and influence anti-tumor immunity is unclear. Here, we identify the GTPase-activating protein (GAP) Rasal1 as a novel TCR-ZAP-70 binding protein that negatively regulates T-cell activation and tumor immunity. Rasal1 inhibits via two pathways, the binding and inhibition of the kinase domain of ZAP-70, and GAP inhibition of the p21ras-ERK pathway. It is expressed in activated CD4 + and CD8 + T-cells, and inhibits CD4 + T-cell responses to antigenic peptides presented by dendritic cells as well as CD4 + T-cell responses to peptide antigens in vivo. Furthermore, siRNA reduction of Rasal1 expression in T-cells shrinks B16 melanoma and EL-4 lymphoma tumors, concurrent with an increase in CD8 + tumor-infiltrating T-cells expressing granzyme B and interferon γ-1. Our findings identify ZAP-70-associated Rasal1 as a new negative regulator of T-cell activation and tumor immunity.


Assuntos
Proteínas Ativadoras de GTPase/imunologia , Proteínas Ativadoras de GTPase/metabolismo , Melanoma Experimental/imunologia , Linfócitos T/imunologia , Proteína-Tirosina Quinase ZAP-70/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas Ativadoras de GTPase/genética , Ativação Linfocitária , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Domínios Proteicos , RNA Interferente Pequeno , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia , Proteína-Tirosina Quinase ZAP-70/genética
8.
Semin Immunol ; 42: 101295, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604533

RESUMO

The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.


Assuntos
Quinase 3 da Glicogênio Sintase/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores
10.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
11.
Sci Rep ; 9(1): 10462, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320682

RESUMO

While the immune cell adaptor protein SKAP1 mediates LFA-1 activation induced by antigen-receptor (TCR/CD3) ligation on T-cells, it is unclear whether the adaptor interacts with other mediators of T-cell function. In this context, the serine/threonine kinase, polo-like kinase (PLK1) regulates multiple steps in the mitotic and cell cycle progression of mammalian cells. Here, we show that SKAP1 is phosphorylated by and binds to PLK1 for the optimal cycling of T-cells. PLK1 binds to the N-terminal residue serine 31 (S31) of SKAP1 and the interaction is needed for optimal PLK1 kinase activity. Further, siRNA knock-down of SKAP1 reduced the rate of T-cell division concurrent with a delay in the expression of PLK1, Cyclin A and pH3. Reconstitution of these KD cells with WT SKAP1, but not the SKAP1 S31 mutant, restored normal cell division. SKAP1-PLK1 binding is dynamically regulated during the cell cycle of T-cells. Our findings identify a novel role for SKAP1 in the regulation of PLK1 and optimal cell cycling needed for T-cell clonal expansion in response to antigenic activation.

13.
Front Immunol ; 9: 2737, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30542345

RESUMO

CTLA-4 is a co-receptor on T-cells that controls peripheral tolerance and the development of autoimmunity. Immune check-point blockade (ICB) uses monoclonal antibodies (MAbs) to block the binding of inhibitory receptors (IRs) to their natural ligands. A humanized antibody to CTLA-4 was first approved clinically followed by the use of antibody blockade against PD-1 and its ligand PD-L1. Effective anti-tumor immunity requires the activation of tumor-specific effector T-cells, the blockade of regulatory cells and the migration of T-cells into the tumor. Here, we review data implicating CTLA-4 and PD-1 in the motility of T-cells with a specific reference to the potential exploitation of these pathways for more effective tumor infiltration and eradication.


Assuntos
Antígeno CTLA-4/imunologia , Movimento Celular/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais/imunologia , Autoimunidade/imunologia , Humanos , Imunoterapia/métodos
14.
BMC Res Notes ; 11(1): 869, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522503

RESUMO

OBJECTIVE: Immune cell adaptor protein SKAP1 couples the antigen-receptor (TCR/CD3) with the activation of LFA-1 adhesion in T-cells. Previous work by ourselves and others have shown that SKAP1 can directly bind to other adaptors such as ADAP and RapL. However, it has been unclear whether SKAP1 can form homodimers with itself and the regions within SKAP1 that mediated homodimer formation. RESULTS: Here, we show that SKAP1 and SKAP2 form homodimers in cells. Homodimer formation of immune adaptor protein SKAP1 (SKAP-55) are mediated by residues A17 to L21 in the SKAP1 N-terminal region. SKAP1 dimer formation was not needed for its binding to RapL. These data indicate that the pathway linking SKAP1 to RapL is not dependent on the homo-dimerization of SKAP1.


Assuntos
Fosfoproteínas/química , Fosfoproteínas/metabolismo , Multimerização Proteica , Humanos , Ligação Proteica , Reprodutibilidade dos Testes , Proteínas rap1 de Ligação ao GTP/metabolismo
15.
Cancer Res ; 78(3): 706-717, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29055015

RESUMO

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3α/ß, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/ß (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3α/ß reduced PD-1 expression on CD8+ T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T cells. Finally, the adoptive transfer of T cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies.Significance: These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. Cancer Res; 78(3); 706-17. ©2017 AACR.


Assuntos
Anticorpos Bloqueadores/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Linfócitos do Interstício Tumoral/imunologia , Linfoma/prevenção & controle , Melanoma Experimental/prevenção & controle , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Apoptose , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma/imunologia , Linfoma/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas
16.
Nat Commun ; 8: 16001, 2017 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-28699640

RESUMO

Lymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering. Although increased affinity mediates adhesion, LFA-1 cross-linking induced the association and activation of the protein-tyrosine kinases FAK1/PYK1 that phosphorylated LAT selectively on a single Y-171 site for the binding to adaptor complex GRB-2-SKAP1. LAT-GRB2-SKAP1 complexes were distinct from canonical LAT-GADs-SLP-76 complexes. LFA-1 cross-linking increased the presence of LAT-GRB2-SKAP1 complexes relative to LAT-GADs-SLP-76 complexes. LFA-1-FAK1 decreased T-cell-dendritic cell (DC) dwell times dependent on LAT-Y171, leading to reduced DO11.10 T cell binding to DCs and proliferation to OVA peptide. Overall, our findings outline a new model for LFA-1 in which the integrin can mediate both adhesion and de-adhesion events dependent on receptor cross-linking.


Assuntos
Quinase 1 de Adesão Focal/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Linfócitos T/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Dendríticas/fisiologia , Proteína Adaptadora GRB2/metabolismo , Humanos , Células Jurkat , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Fosforilação
17.
Immunity ; 46(4): 529-531, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28423334

RESUMO

The identity of PD-1 dependency on other receptors and signaling has been unclear. In a recent issue of Science, Hui et al. (2017) and Kamphorst et al. (2017) now show that CD28 expression is a target of PD-1-associated phosphatases and is needed for T cell expansion in anti-PD-1 immunotherapy.


Assuntos
Antígenos CD28 , Linfócitos T , Ciclo Celular , Humanos , Imunoterapia , Transdução de Sinais
18.
J Biol Chem ; 292(15): 6281-6290, 2017 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-28188290

RESUMO

The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, "3Y") as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ativação Linfocitária/fisiologia , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Motivos de Aminoácidos , Substituição de Aminoácidos , Animais , Humanos , Células Jurkat , Camundongos , Mutação de Sentido Incorreto , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fosforilação/fisiologia , Domínios Proteicos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Tirosina
19.
Artigo em Inglês | MEDLINE | ID: mdl-31544130

RESUMO

T-cell activation is mediated by a combination of signals from the antigen receptor (TCR) and co-receptors such as CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death antigen 1 (PD-1), CD28H and others. Each is a member of the CD28 receptor gene family. CD28 sends positive signals that promote T-cell responses, while CTLA-4 and PD-1 limit responses. It is the balance between these positive and negative signals that determines the amplitude and level of T-cell responses. The regulatory role of other family members is also becoming the focus of increasing interest. The function of certain CD28 family members such as CTLA-4 and PD-1 is dependent the expression of CD28. Together, these findings have important implications in generation of immune responses and the application of anti-receptor blocking reagents in immunotherapy.

20.
Front Immunol ; 8: 1653, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29312284

RESUMO

The rescue of exhausted CD8+ cytolytic T-cells (CTLs) by anti-Programmed Cell Death-1 (anti-PD-1) blockade has been found to require CD28 expression. At the same time, we have shown that the inactivation of the serine/threonine kinase glycogen synthase kinase (GSK)-3α/ß with small-interfering RNAs (siRNAs) and small molecule inhibitors (SMIs) specifically down-regulates PD-1 expression for enhanced CD8+ CTL function and clearance of tumors and viral infections. Despite this, it has been unclear whether the GSK-3α/ß pathway accounts for CD28 costimulation of CD8+ CTL function. In this article, we show that inactivation of GSK-3α/ß through siRNA or by SMIs during priming can substitute CD28 co-stimulation in the potentiation of cytotoxic CD8+ CTL function against the EL-4 lymphoma cells expressing OVA peptide. The effect was seen using several structurally distinct GSK-3 SMIs and was accompanied by an increase in Lamp-1 and GZMB expression. Conversely, CD28 crosslinking obviated the need for GSK-3α/ß inhibition in its enhancement of CTL function. Our findings support a model where GSK-3 is the central cosignal for CD28 priming of CD8+ CTLs in anti-PD-1 immunotherapy.

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