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1.
Nat Commun ; 12(1): 2055, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824342

RESUMEN

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.


Asunto(s)
Antivirales/farmacología , /virología , Reacciones Cruzadas/inmunología , Inmunoensayo/métodos , Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Citocinas/metabolismo , Células HEK293 , Personal de Salud , Humanos , Inmunoglobulina G/inmunología , Memoria Inmunológica , Interferón gamma/metabolismo , Pandemias , Péptidos/metabolismo , /efectos de los fármacos
2.
Cell ; 184(7): 1804-1820.e16, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33691139

RESUMEN

SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Linfocitos T CD8-positivos , Fragmentos Fc de Inmunoglobulinas/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Células CHO , /terapia , Chlorocebus aethiops , Cricetulus , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Células Vero , Carga Viral
3.
Signal Transduct Target Ther ; 6(1): 126, 2021 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-33758164

RESUMEN

The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interleucina-7/inmunología , Proteínas/inmunología , ARN Largo no Codificante/inmunología , Vesículas Secretoras/inmunología , Transducción de Señal/inmunología , Animales , Transporte Biológico Activo , Linfocitos T CD8-positivos/patología , Humanos , Memoria Inmunológica , Ratones , Vesículas Secretoras/patología
4.
Nat Commun ; 12(1): 1921, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771991

RESUMEN

Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.


Asunto(s)
Enfermedad de Crohn/inmunología , Linfocitos Intraepiteliales/inmunología , Análisis de la Célula Individual/métodos , Subgrupos de Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Enfermedad de Crohn/patología , Perfilación de la Expresión Génica/métodos , Humanos , Linfocitos Intraepiteliales/metabolismo , Recuento de Linfocitos , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
5.
Front Immunol ; 12: 636768, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777028

RESUMEN

Understanding the causes of the diverse outcome of COVID-19 pandemic in different geographical locations is important for the worldwide vaccine implementation and pandemic control responses. We analyzed 42 unexposed healthy donors and 28 mild COVID-19 subjects up to 5 months from the recovery for SARS-CoV-2 specific immunological memory. Using HLA class II predicted peptide megapools, we identified SARS-CoV-2 cross-reactive CD4+ T cells in around 66% of the unexposed individuals. Moreover, we found detectable immune memory in mild COVID-19 patients several months after recovery in the crucial arms of protective adaptive immunity; CD4+ T cells and B cells, with a minimal contribution from CD8+ T cells. Interestingly, the persistent immune memory in COVID-19 patients is predominantly targeted towards the Spike glycoprotein of the SARS-CoV-2. This study provides the evidence of both high magnitude pre-existing and persistent immune memory in Indian population. By providing the knowledge on cellular immune responses to SARS-CoV-2, our work has implication for the development and implementation of vaccines against COVID-19.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Linfocitos B/virología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , /diagnóstico , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto Joven
6.
Front Immunol ; 12: 598778, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717077

RESUMEN

Emerging infectious diseases (EIDs) caused by viruses are increasing in frequency, causing a high disease burden and mortality world-wide. The COVID-19 pandemic caused by the novel SARS-like coronavirus (SARS-CoV-2) underscores the need to innovate and accelerate the development of effective vaccination strategies against EIDs. Human leukocyte antigen (HLA) molecules play a central role in the immune system by determining the peptide repertoire displayed to the T-cell compartment. Genetic polymorphisms of the HLA system thus confer a strong variability in vaccine-induced immune responses and may complicate the selection of vaccine candidates, because the distribution and frequencies of HLA alleles are highly variable among different ethnic groups. Herein, we build on the emerging paradigm of rational epitope-based vaccine design, by describing an immunoinformatics tool (Predivac-3.0) for proteome-wide T-cell epitope discovery that accounts for ethnic-level variations in immune responsiveness. Predivac-3.0 implements both CD8+ and CD4+ T-cell epitope predictions based on HLA allele frequencies retrieved from the Allele Frequency Net Database. The tool was thoroughly assessed, proving comparable performances (AUC ~0.9) against four state-of-the-art pan-specific immunoinformatics methods capable of population-level analysis (NetMHCPan-4.0, Pickpocket, PSSMHCPan and SMM), as well as a strong accuracy on proteome-wide T-cell epitope predictions for HIV-specific immune responses in the Japanese population. The utility of the method was investigated for the COVID-19 pandemic, by performing in silico T-cell epitope mapping of the SARS-CoV-2 spike glycoprotein according to the ethnic context of the countries where the ChAdOx1 vaccine is currently initiating phase III clinical trials. Potentially immunodominant CD8+ and CD4+ T-cell epitopes and population coverages were predicted for each population (the Epitope Discovery mode), along with optimized sets of broadly recognized (promiscuous) T-cell epitopes maximizing coverage in the target populations (the Epitope Optimization mode). Population-specific epitope-rich regions (T-cell epitope clusters) were further predicted in protein antigens based on combined criteria of epitope density and population coverage. Overall, we conclude that Predivac-3.0 holds potential to contribute in the understanding of ethnic-level variations of vaccine-induced immune responsiveness and to guide the development of epitope-based next-generation vaccines against emerging pathogens, whose geographic distributions and populations in need of vaccinations are often well-defined for regional epidemics.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/metabolismo , Grupos Étnicos , Antígenos HLA/metabolismo , Proteómica/métodos , Glicoproteína de la Espiga del Coronavirus/metabolismo , /epidemiología , Enfermedades Transmisibles Emergentes , Epítopos de Linfocito T/genética , Antígenos HLA/genética , Humanos , Inmunogenicidad Vacunal , Aplicaciones de la Informática Médica , Pandemias/prevención & control , Polimorfismo Genético , Unión Proteica , Programas Informáticos , Glicoproteína de la Espiga del Coronavirus/genética
7.
Front Immunol ; 12: 640644, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33717195

RESUMEN

Infection with SARS-CoV-2 can lead to Coronavirus disease-2019 (COVID-19) and result in severe acute respiratory distress syndrome (ARDS). Recent reports indicate an increased rate of fungal coinfections during COVID-19. With incomplete understanding of the pathogenesis and without any causative therapy available, secondary infections may be detrimental to the prognosis. We monitored 11 COVID-19 patients with ARDS for their immune phenotype, plasma cytokines, and clinical parameters on the day of ICU admission and on day 4 and day 7 of their ICU stay. Whole blood stimulation assays with lipopolysaccharide (LPS), heat-killed Listeria monocytogenes (HKLM), Aspergillus fumigatus, and Candida albicans were used to mimic secondary infections, and changes in immune phenotype and cytokine release were assessed. COVID-19 patients displayed an immune phenotype characterized by increased HLA-DR+CD38+ and PD-1+ CD4+ and CD8+ T cells, and elevated CD8+CD244+ lymphocytes, compared to healthy controls. Monocyte activation markers and cytokines IL-6, IL-8, TNF, IL-10, and sIL2Rα were elevated, corresponding to monocyte activation syndrome, while IL-1ß levels were low. LPS, HKLM and Aspergillus fumigatus antigen stimulation provoked an immune response that did not differ between COVID-19 patients and healthy controls, while COVID-19 patients showed an attenuated monocyte CD80 upregulation and abrogated release of IL-6, TNF, IL-1α, and IL-1ß toward Candida albicans. This study adds further detail to the characterization of the immune response in critically ill COVID-19 patients and hints at an increased susceptibility for Candida albicans infection.


Asunto(s)
Aspergillus fumigatus/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Candida albicans/inmunología , Listeria monocytogenes/inmunología , /fisiología , Anciano , Células Cultivadas , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo
8.
Sci Immunol ; 6(57)2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664060

RESUMEN

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T , Antígenos HLA-A/inmunología , Inmunidad Celular , Mutación , Linfocitos T CD8-positivos/patología , /inmunología , Proliferación Celular , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Interferón gamma/inmunología , Péptidos/genética , Péptidos/inmunología , /inmunología
9.
Nat Commun ; 12(1): 1359, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649336

RESUMEN

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Inmunomodulación , Inmunoterapia , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Femenino , Proteínas Inmovilizadas/metabolismo , Inmunidad , Células Asesinas Naturales/inmunología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Linfocitos T/inmunología
10.
Nat Commun ; 12(1): 1439, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664251

RESUMEN

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Infecciones por Citomegalovirus/tratamiento farmacológico , Hepatitis A/prevención & control , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/inmunología , Hepatitis A/inmunología , Hepatitis A/virología , Humanos , Memoria Inmunológica/inmunología , Melanoma/tratamiento farmacológico , Valganciclovir/uso terapéutico , Carga Viral
11.
Nat Commun ; 12(1): 1428, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674591

RESUMEN

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of 'immune silence' in patients with critical COVID-19.


Asunto(s)
/inmunología , /inmunología , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Células Mieloides/inmunología , Neutrófilos/inmunología , Linfocitos T/inmunología
12.
Nat Commun ; 12(1): 1724, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741972

RESUMEN

T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4+ and CD8+ T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Virosis/diagnóstico , Anticuerpos Antivirales/inmunología , Infecciones Asintomáticas , Estudios de Casos y Controles , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología
13.
Nat Commun ; 12(1): 1858, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767151

RESUMEN

Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells.


Asunto(s)
Neoplasias de la Mama/terapia , Factor 3 Regulador del Interferón/inmunología , Melanoma/terapia , Viroterapia Oncolítica , Proteínas Serina-Treonina Quinasas/inmunología , Microambiente Tumoral/inmunología , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Inmunidad Innata/inmunología , Interferón Tipo I/inmunología , Helicasa Inducida por Interferón IFIH1/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal/inmunología , Células TH1/inmunología
14.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-33669921

RESUMEN

CD8+ T cells are the main effector cells of anti-cancer immune response that can be regulated by various costimulatory and coinhibitory molecules, including members of the B7 family. B7 homolog 3 (B7-H3) appears as a promising marker for immunotherapy; however, its significance in gastric cancer (GC) is unclear yet. We evaluated the spatial distribution of CD8+ T cells in relation to the expression of B7-H3 by double immunohistochemical staining. The level of B7-H3 intensity was scored manually (0-3) and dichotomized into B7-H3-low and B7-H3-high groups. The distribution and density of CD8+ T cells was analysed using whole slide digital imaging. B7-H3 was expressed mainly in the stromal compartment of GC (n = 73, 76% of all cases). Tumours with high expression of B7-H3 showed larger spatial differences of CD8+ T cells (86.4/mm2 in tumour centre vs. 414.9/mm2 in invasive front) when compared to B7-H3-low group (157.7/mm2 vs. 218.7/mm2, respectively) (p < 0.001). This study provides insight into the expression pattern of B7-H3 in GC of Western origin. In GCs with higher level of B7-H3 expression, CD8+ T cells were spatially suppressed in the tumour centre suggesting that B7-H3 might be involved in tumour escape mechanisms from the immune response.


Asunto(s)
Antígenos B7/metabolismo , Linfocitos T CD8-positivos/inmunología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Anciano , Femenino , Humanos , Recuento de Linfocitos , Masculino , Células del Estroma/metabolismo , Análisis de Supervivencia
15.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671258

RESUMEN

We evaluated the abscopal effect of re-implantation of liquid nitrogen-treated tumor-bearing bone grafts and the synergistic effect of anti-PD-1 (programmed death-1) therapy using a bone metastasis model, created by injecting MMT-060562 cells into the bilateral tibiae of 6-8-week-old female C3H mice. After 2 weeks, the lateral tumors were treated by excision, cryotreatment using liquid nitrogen, excision with anti-PD-1 treatment, and cryotreatment with anti-PD-1 treatment. Anti-mouse PD-1 4H2 was injected on days 1, 6, 12, and 18 post-treatment. The mice were euthanized after 3 weeks; the abscopal effect was evaluated by focusing on growth inhibition of the abscopal tumor. The re-implantation of frozen autografts significantly inhibited the growth of the remaining abscopal tumors. However, a more potent abscopal effect was observed in the anti-PD-1 antibody group. The number of CD8+ T cells infiltrating the abscopal tumor and tumor-specific interferon-γ (IFN-γ)-producing spleen cells increased in the liquid nitrogen-treated group compared with those in the excision group, with no significant difference. The number was significantly higher in the anti-PD-1 antibody-treated group than in the non-treated group. Overall, re-implantation of tumor-bearing frozen autograft has an abscopal effect on abscopal tumor growth, although re-implantation of liquid nitrogen-treated bone grafts did not induce a strong T-cell response or tumor-suppressive effect.


Asunto(s)
Autoinjertos/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , /uso terapéutico , Animales , Neoplasias Óseas/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinogénesis/patología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C3H , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Esplenomegalia/patología , Carga Tumoral/efectos de los fármacos
16.
Science ; 371(6535)2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33737461

RESUMEN

Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rß, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rß binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.


Asunto(s)
Interleucina-10/química , Interleucina-10/metabolismo , Animales , Sitios de Unión , Linfocitos T CD8-positivos/inmunología , Línea Celular , Microscopía por Crioelectrón , Citocinas/metabolismo , Evolución Molecular Dirigida , Humanos , Inflamación , Interleucina-10/agonistas , Subunidad alfa del Receptor de Interleucina-10/química , Subunidad alfa del Receptor de Interleucina-10/metabolismo , Subunidad beta del Receptor de Interleucina-10/química , Subunidad beta del Receptor de Interleucina-10/metabolismo , Activación de Macrófagos , Ratones , Modelos Moleculares , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Unión Proteica , Ingeniería de Proteínas , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Factor de Transcripción STAT3/metabolismo , Sepsis/inmunología , Transducción de Señal
17.
Nat Commun ; 12(1): 1503, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33686071

RESUMEN

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.


Asunto(s)
Neoplasias Encefálicas/inmunología , Líquido Cefalorraquídeo/inmunología , Leucocitos , Microambiente Tumoral/inmunología , Adenocarcinoma del Pulmón , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Linfocitos T CD8-positivos/inmunología , Humanos , Neoplasias Pulmonares , Pronóstico
18.
Methods Mol Biol ; 2265: 645-654, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704745

RESUMEN

Expression of chimeric antigen receptors can redirect T cell specificity and allow for MHC-independent recognition of melanoma associated antigens. Retroviral transduction is used to express chimeric antigen receptor constructs in murine CD4+ and CD8+ T cells. Here we describe the production of retroviral supernatants and the activation, transduction, expansion, and selection of murine T cells expressing the chimeric-PD1 receptor. This protocol can be modified for any murine chimeric antigen receptor construct.


Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Inmunoterapia Adoptiva , Melanoma Experimental , Receptores Quiméricos de Antígenos , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Humanos , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología
19.
Nat Commun ; 12(1): 1669, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723257

RESUMEN

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Anciano , Anciano de 80 o más Años , Biomarcadores , Linfocitos T CD8-positivos/inmunología , Femenino , Granzimas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Receptores CXCR4/metabolismo
20.
PLoS One ; 16(3): e0248061, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33730022

RESUMEN

Developing an efficacious vaccine for SARS-CoV-2 infection is critical to stemming COVID-19 fatalities and providing the global community with immune protection. We have used a bioinformatic approach to aid in designing an epitope peptide-based vaccine against the spike protein of the virus. Five antigenic B cell epitopes with viable antigenicity and a total of 27 discontinuous B cell epitopes were mapped out structurally in the spike protein for antibody recognition. We identified eight CD8+ T cell 9-mers and 12 CD4+ T cell 14-15-mer as promising candidate epitopes putatively restricted by a large number of MHC I and II alleles, respectively. We used this information to construct an in silico chimeric peptide vaccine whose translational rate was highly expressed when cloned in pET28a (+) vector. With our In silico test, the vaccine construct was predicted to elicit high antigenicity and cell-mediated immunity when given as a homologous prime-boost, triggering of toll-like receptor 5 by the adjuvant linker. The vaccine was also characterized by an increase in IgM and IgG and an array of Th1 and Th2 cytokines. Upon in silico challenge with SARS-CoV-2, there was a decrease in antigen levels using our immune simulations. We, therefore, propose that potential vaccine designs consider this approach.


Asunto(s)
/inmunología , Epítopos de Linfocito T/inmunología , Inmunogenicidad Vacunal/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de Subunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Biología Computacional/métodos , Citocinas/inmunología , Epítopos de Linfocito B/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunidad Celular/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Simulación del Acoplamiento Molecular , Péptidos/inmunología
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