Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 972
Filtrar
1.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
2.
Anticancer Res ; 41(7): 3281-3285, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230122

RESUMO

BACKGROUND/AIM: Recent studies have indicated that natural killer (NK) cells present in peripheral blood mononuclear cells (PBMCs) might be responsible for the somewhat poor outcome of clinical trials conducted with the NK cell line NK-92, as well as chimeric antigen receptor-modified NK-92 cells against leukemias and lymphomas. These NK cells and how their cytotoxic profiles can be altered by some common gamma chain receptor-dependent cytokines or by removal of CD4+ cells have been addressed herein. MATERIALS AND METHODS: A time-resolved fluorometric assay using 2.2':6'.2"-terpyridine-6.6"-dicarboxylic acid-labeled NK-92 or K562 as target cells was used for measuring the cytotoxic activity of cytokine-treated PBMCs and purified NK cells. RESULTS: Pre-incubation with 25 ng/ml interleukin 12 (IL-12), IL-15 or IL-21 for 72 h increased NK cell activity against K562 cells by more than 90% (1:25 target:effector ratio), whereas the corresponding NK cell activity against NK-92 cells was reduced by 15.9±0.1% by IL-12 and 50.6±2.9% by IL-15 compared to cells treated with medium alone. IL-7, on the other hand, increased NK activity against K562 to a much smaller extent (10.4±0.4%) and inhibited NK-92 cell lysis by 15.2±0.3%. Interestingly, similar amounts of IL-2 potentiated NK cell activity against both K562 and NK-92 cells by 50.9±0.5% and 14.3±0.9%, respectively. Purification of NK cells with magnetic beads demonstrated that NK cells indeed were responsible for the observed cytotoxic activity against both NK-92 cells (58.5±9.10%, 1:100 target:effector ratio) and K562 cells (81.6±9.57%, 1:100 target:effector ratio). Elimination of CD4+ cells from PBMCs did not alter the NK activity profile. CONCLUSION: This study highlights a problem that might arise with immune-based NK-92 and chimeric antigen receptor-transduced NK-92 cell therapies and pinpoints the need for evaluating new NK-like cell lines.


Assuntos
Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Linfoma/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Interleucinas/imunologia , Células K562 , Leucócitos Mononucleares/imunologia , Receptores de Antígenos Quiméricos/imunologia
3.
Nat Commun ; 12(1): 4474, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294714

RESUMO

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103-CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transferência Adotiva , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células Estreladas do Fígado/imunologia , Humanos , Memória Imunológica , Interleucina-15/imunologia , Cirrose Hepática/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/terapia , Receptores CCR5/imunologia , Adulto Jovem
4.
J Exp Med ; 218(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33988715

RESUMO

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This "participant-derived xenograft" model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Xenoenxertos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Células HEK293 , Infecções por HIV/virologia , Xenoenxertos/virologia , Humanos , Imunoterapia/métodos , Interleucina-15/imunologia , Camundongos , Mutação/imunologia , Viremia/imunologia , Viremia/virologia , Replicação Viral/imunologia
5.
Front Immunol ; 12: 646159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953717

RESUMO

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rß. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.


Assuntos
Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Interleucina-15/imunologia , Proteínas Recombinantes de Fusão/imunologia , Animais , Células CHO , Cricetulus , Feminino , Genes de Cadeia Pesada de Imunoglobulina , Humanos , Imunoglobulina G/química , Interleucina-15/química , Interleucina-15/genética , Interleucina-15/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Multimerização Proteica , Estabilidade Proteica
7.
Nat Commun ; 12(1): 2029, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795689

RESUMO

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor ß chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1ß induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1ß to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1ßR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.


Assuntos
Citocinas/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células T Invariantes Associadas à Mucosa/citologia , Células T Invariantes Associadas à Mucosa/metabolismo , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
8.
Cell Immunol ; 363: 104314, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33677140

RESUMO

T cell-based adoptive cell transfer therapy is now clinically used to fight cancer with CD19-targeting chimeric antigen receptor T cells. The use of other T cell-based immunotherapies relying on antigen-specific T cells, genetically modified or not, is expanding in various neoplastic diseases. T cell manufacturing has evolved through sophisticated processes to produce T cells with improved therapeutic potential. Clinical-grade manufacturing processes associated with these therapies must meet pharmaceutical requirements and therefore be standardized. Here, we focus on the use of cytokines to expand minimally differentiated T cells, as well as their standardization and harmonization in research and clinical settings.


Assuntos
Interleucina-15/administração & dosagem , Interleucina-15/imunologia , Interleucina-7/administração & dosagem , Interleucina-7/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD19/imunologia , Antígenos CD28/imunologia , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citotoxicidade Imunológica , Humanos , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Ativação Linfocitária , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
9.
Med Oncol ; 38(3): 30, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33598783

RESUMO

Adoptive transfer of γδ T cells is an attractive approach for cell-based immunotherapy in treatment of renal cell carcinoma (RCC). Interleukin-15 (IL-15) is the key physiological cytokine that regulates γδ T cell differentiation, proliferation and survival. In this work, we determined that IL-15 have the capacity to enhance the anti-tumoral functions of γδ T cells. IL-15 can induce the upregulation of cytotoxicity-associated molecules on the γδ T cell surface, incite γδ T cell proliferation and decrease apoptosis. Moreover, the enhanced cytotoxicity of IL-15-induced γδ T cell was dependent on the interaction of NKG2D and MICA. Most importantly, we found that IL-15-induced γδ T cells effectively suppressed the tumor growth in vivo and prolonged the survival time of RCC-bearing patient­derived xenograft (PDX) mice. These results are important for the prospective use of γδ T cells in clinical practice when designing novel cell-based immunotherapies against RCC.


Assuntos
Carcinoma de Células Renais/terapia , Imunoterapia Adotiva/métodos , Interleucina-15/imunologia , Neoplasias Renais/terapia , Linfócitos T/transplante , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Leucócitos Mononucleares , Camundongos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33531712

RESUMO

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Assuntos
COVID-19/imunologia , Interferon-alfa/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Lavagem Broncoalveolar , Estudos de Casos e Controles , Chlorocebus aethiops , Estudos de Coortes , Feminino , França , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Célula Única , Células Vero , Adulto Jovem
11.
JCI Insight ; 6(1)2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33232303

RESUMO

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.


Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Corticosteroides/uso terapêutico , Adulto , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Biomarcadores , COVID-19/genética , COVID-19/terapia , Calgranulina B/genética , Calgranulina B/imunologia , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ferritinas/genética , Ferritinas/imunologia , Perfilação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lactoferrina/genética , Lactoferrina/imunologia , Lipocalina-2/genética , Lipocalina-2/imunologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Análise Multivariada , NF-kappa B/genética , NF-kappa B/imunologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-33323466

RESUMO

OBJECTIVE: We posit that interleukin-15 (IL-15) is a relevant contributor to MS pathobiology as this cytokine is elevated in the CNS and periphery of patients with MS. We aim to investigate (1) the impact of IL-15 on T lymphocytes from patients with MS and (2) the in vivo role of IL-15 using the experimental autoimmune encephalomyelitis (EAE) mouse model. METHODS: We compared the impact of IL-15 on T lymphocytes obtained from untreated patients with MS (relapsing-remitting, secondary progressive, and primary progressive) to cells from age/sex-matched healthy controls (HCs) using multiparametric flow cytometry and in vitro assays. We tested the effects of peripheral IL-15 administration after EAE disease onset in C57BL/6 mice. RESULTS: IL-15 triggered STAT5 signaling in an elevated proportion of T cells from patients with MS compared with HCs. This cytokine also enhanced the production of key proinflammatory cytokines (interferon γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17, and tumor necrosis factor) by T cells from both MS and controls, but these effects were more robust for the production of IL-17 and GM-CSF in T-cell subsets from patients with MS. At the peak of EAE disease, the proportion of CD4+ and CD8+ T cells expressing CD122+, the key signaling IL-15 receptor chain, was enriched in the CNS compared with the spleen. Finally, peripheral administration of IL-15 into EAE mice after disease onset significantly aggravated clinical scores and increased the number of inflammatory CNS-infiltrating T cells long term after stopping IL-15 administration. CONCLUSIONS: Our results underscore that IL-15 contributes to the amplification of T-cell inflammatory properties after disease onset in both MS and EAE.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-15/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Front Immunol ; 11: 532684, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117338

RESUMO

We generated an NOD/Shi-scid-IL2Rγ null (NOG) mouse deficient for the Fcer1g and Fcgr2b genes (NOG-FcγR-/- mice), in which monocytes/macrophages do not express activating (FcγRI, III, and IV) or inhibitory (FcγRIIB) Fcγ receptors. Antibody-dependent cellular cytotoxicity (ADCC) by innate immune cells was strongly reduced in this strain. Thus, while the growth of xenogeneic human tumors engrafted in conventional NOG mice was suppressed by innate cells upon specific antibody treatment, such growth inhibition was abrogated in NOG-FcγR-/- mice. Using this novel strain, we further produced NOG-FcγR-/--mice expressing human IL-15 (NOG-FcγR-/--hIL-15 Tg). The mice inherited unique features from each strain, i.e., the long-term sustenance of human natural killer (NK) cells, and the elimination of mouse innate cell-mediated ADCC. As a result, segregation of human NK cell-mediated ADCC from mouse cell-mediated ADCC was possible in the NOG-FcγR-/--hIL-15 Tg mice. Our results suggest that NOG-FcγR-/--hIL-15 Tg mice are useful for validating the in vivo function of antibody drug candidates.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Proteínas de Transporte/genética , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Receptores de IgG/deficiência , Animais , Proteínas de Transporte/imunologia , Humanos , Interleucina-15/genética , Camundongos , Camundongos Knockout , Receptores de IgG/imunologia
14.
J Immunol ; 205(11): 2968-2978, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33106337

RESUMO

Effector memory (EM) CD8+ T cells expressing lower levels of IL-7R α (IL-7Rαlow) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. In this study, we demonstrate that human IL-7Rαlow EM CD8+ T cells are naturally occurring anergic cells in vivo and impaired in proliferation and IL-2 production but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rαlow EM CD8+ T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming toward glycolysis, a process required for the proliferation of T cells. However, IL-7Rαlow EM CD8+ T cells can proliferate with TCR stimulation in the presence of IL-2 and IL-15, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glicólise/imunologia , Receptores de Interleucina-7/imunologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Cultivadas , Fator de Transcrição GATA3/imunologia , Voluntários Saudáveis , Humanos , Memória Imunológica/imunologia , Interleucina-15/imunologia , Células Jurkat , Proteínas Proto-Oncogênicas c-myc/imunologia , Transdução de Sinais/imunologia
15.
Front Immunol ; 11: 1868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983105

RESUMO

Cancer immunotherapy has shown great advances during recent years, but it has yet to reach its full potential in all cancer types. Adoptive cell therapy (ACT) is now an approved treatment option for certain hematological cancers and has also shown success for some solid cancers. Still, benefit and eligibility do not extend to all patients. ACT with Vγ9Vδ2 T cells is a promising approach to overcome this hurdle. In this study, we aimed to explore the effect of different cytokine conditions on the expansion of Vγ9Vδ2 T cells in vitro. We could show that Vγ9Vδ2 T cell expansion is feasible with two different cytokine conditions: (a) 1,000 U/ml interleukin (IL)-2 and (b) 100 U/ml IL-2 + 100 U/ml IL-15. We did not observe differences in expansion rate or Vγ9Vδ2 T cell purity between the conditions; however, IL-2/IL-15-expanded Vγ9Vδ2 T cells displayed enhanced cytotoxicity against tumor cells, also in hypoxia. While this increase in killing capacity was not reflected in natural killer (NK) cell marker or activation marker expression, we demonstrated that IL-2/IL-15-expanded Vγ9Vδ2 T cells were characterized by an increased expression of perforin, granzyme B, and granulysin compared to IL-2-expanded cells. These cytotoxic molecules were not only increased in a resting state, but also released to a greater extent upon target recognition. In contrast, CD107a and cytokine expression did not differ between expansion conditions. However, IL-2/IL-15-expanded Vγ9Vδ2 T cells showed higher levels of transcription factor T-bet expression, which could indicate that T-bet and cytotoxic molecule levels confer the increased cytotoxicity. These results advocate the inclusion of IL-15 into ex vivo Vγ9Vδ2 T cell expansion protocols in future clinical studies.


Assuntos
Técnicas de Cultura de Células/métodos , Citotoxicidade Imunológica/imunologia , Imunoterapia Adotiva , Interleucina-15/farmacologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interleucina-15/imunologia , Interleucina-2/imunologia , Interleucina-2/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T/efeitos dos fármacos
16.
Cell Immunol ; 357: 104213, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32977157

RESUMO

The development of T cell lymphomas in mice that constitutively express a single T cell receptor is surveilled by the action of NK cells. We investigated the effects of engaging the lymphoma TCR in this mouse model. We stimulated lymphoma cells expressing an ovalbumin-specific TCR in vivo using listeria monocytogenes as a vehicle. Infections with listeria expressing ovalbumin but not with control bacteria caused a stable change in lymphoma cells that allowed its growth in mice with normal NK cells. TCR engagement furthermore enhanced lymphoma growth in NK-cell-depleted mice suggesting a lymphoma-intrinsic change that lead to accelerated growth. The ability to grow in mice without prior NK cell depletion did not appear to be accompanied by changes in the recognition of lymphoma by NK cells. Rather, lymphoma immunization was associated with a decrease in NK cell numbers: Leukemic phases were observed for all mice starting three to eight weeks after immunizations, and leukemias were succeeded by the disappearance of NK cells from blood. We also observed strong decreases of NK cell numbers in spleens at the time of death. Co-culture experiments showed decreases in the ability of NK cells to proliferate in response to IL-15 when post-immunization lymphoma cells were present in a mechanism that did not require direct cell contact. Together these data suggest that TCR engagement caused intrinsic changes in T cell lymphoma cells resulting in both accelerated in vivo growth and in the secretion of a factor that caused NK cell disappearance.


Assuntos
Células Matadoras Naturais/imunologia , Linfoma/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Modelos Animais de Doenças , Interleucina-15/imunologia , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Listeria monocytogenes/patogenicidade , Linfoma/metabolismo , Linfoma/patologia , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/genética
17.
Fish Shellfish Immunol ; 107(Pt A): 104-117, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32971272

RESUMO

Interleukin (IL) -15 belongs to the common cytokine receptor γ chain (γC) family and has diverse functions in regulating the development, proliferation and activation of NK and T cells. It activates a hetero-trimeric receptor complex consisting of IL-2Rα, IL-2Rß and a common γ chain (γC). In this study, the full-length cDNA sequences of IL-15 and IL-2Rß were identified in grass carp (Ctenopharyngodon idella, Ci) and their expression profiles analysed. The CiIL-15 and CiIL-2Rß were shown to be broadly expressed in tissues, with the highest levels detected in the spleen. Moreover, the CiIL-15 and CiIL-2Rß were modulated in primary head kidney leucocytes (HKLs) and splenocytes by immunostimulants and cytokines, and in the head kidney and spleen of fish after infection of Flavobacterium columnare and grass carp reovirus. The bioactivity of bacteria derived recombinant CiIL-15 protein was evaluated in the primary leucocytes. The CiIL-15 was shown to induce signature genes of type 1 immune response (IFN-γ and T-bet) and NK cell activation (perforin and Eomesa), whilst exhibiting inhibitory effects on the genes involved in the type 2 immune response (IL-4/13, IL-10 and Gata3). Our data suggest that IL-15 is a key regulator in promoting the type 1 immune response and NK cell activation in fish.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Perciformes/genética , Perciformes/imunologia , Imunidade Adaptativa/genética , Sequência de Aminoácidos , Animais , Carpas , Proteínas de Peixes/química , Perfilação da Expressão Gênica/veterinária , Interleucina-15/química , Interleucina-15/genética , Interleucina-15/imunologia , Subunidade beta de Receptor de Interleucina-2/química , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Filogenia , Alinhamento de Sequência/veterinária
18.
J Immunol ; 205(5): 1331-1344, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32747501

RESUMO

Deglycosylated, live-attenuated SIV vaccines elicited protective immune responses against heterologous SIVsmE543-3, which differs from the vaccine strain SIVmac239 to levels similar to those across HIV-1 clades. Two thirds of the vaccinees contained the chronic SIVsmE543-3 infection (controllers), whereas one third did not (noncontrollers). In this study, we investigated immune correlates of heterologous challenge control in rhesus macaques of Burmese origin. Because depletion of CD8+ cells in the controllers by administration of anti-CD8α Ab abrogated the control of viral replication, CD8+ cells were required for the protective immune response. However, classical SIV-specific CD8+ T cells did not account for the protective immune response in all controllers. Instead, IL-15-responding CD8α+ cells, including CD8+ T and NK cells, were significantly higher in the controllers than those in the noncontrollers, before and after vaccination with deglycosylated SIV. It is well established that IL-15 signal transduction occurs through "trans-presentation" in which IL-15 complexed with IL-15Rα on monocytes, macrophages, and dendritic cells binds to IL-15 Rß/γ expressed on CD8+ T and NK cells. Accordingly, levels of IL-15 stimulation were strongly affected by the depletion of monocytes from PBMCs, implying key roles of innate immune cells. These results suggest that intrinsic IL-15 responsiveness may dictate the outcome of protective responses and may lead to optimized formulations of future broadly protective HIV vaccines.


Assuntos
Imunidade Inata/imunologia , Interleucina-15/imunologia , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vacinas Atenuadas/imunologia , Animais , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Macaca mulatta , Masculino , Monócitos/imunologia , Transdução de Sinais/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vacinação/métodos , Carga Viral/imunologia , Replicação Viral/imunologia
19.
Fish Shellfish Immunol ; 106: 404-409, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32800982

RESUMO

Epinephelus coioides is an important economic culture marine fish and is susceptible to various pathogenic diseases. Increasingly evidences showed that miRNAs participated in the regulation of the cell proliferation, differentiation and immune response. MiR-122 has been reported to play an essential role in immune response by triggering an inflammatory reaction. However, the function of miR-122 in response to bacterial infection is unclear in Epinephelus coioides. Herein, we report that miR-122 is involved in response to Aeromonas hydrophila infection of grouper spleen cells (GS). IL-15, IL-6 and IL-1ß are inhibited in overexpression miR-122 GS cells, while induced in silence miR-122 GS cells. In addition, IL-15 is predicted to be the target gene of miR-122, which is further confirmed by LUC. Taken together, we propose that miR-122 regulates the immune response to bacterial infection by triggering IL-15.


Assuntos
Bass/genética , Bass/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucina-15/genética , Interleucina-15/imunologia , Aeromonas hydrophila/fisiologia , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Interleucina-15/química , MicroRNAs/genética , MicroRNAs/metabolismo , Filogenia , Alinhamento de Sequência/veterinária , Baço/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...