Marta Calvet‐Mirabent

Hospital Universitario de La Princesa

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Enrique Martín‐Gayo

Hospital Universitario de La Princesa

Ildefonso Sánchez‐Cerrillo

Hospital Universitario de La Princesa

Francisco Sánchez‐Madrid

Universidad Autónoma de Madrid

Cristina Delgado‐Arévalo

Universidad Autónoma de Madrid

Ilya Tsukalov

Universidad Autónoma de Madrid

Hortensia de la Fuente

Centro de Investigación en Red en Enfermedades Cardiovasculares

María J. Buzón

Vall d'Hebron Institut de Recerca

Arántzazu Alfranca

Hospital Universitario de La Princesa

Isidoro González‐Álvaro

Hospital Universitario de La Princesa

MÁ

María Ángeles Muñoz‐Fernández

Hospital General Universitario Gregorio Marañón

Cooperative Institutions

Universidad Autónoma de Madrid

Hospital Universitario de La Princesa

Instituto de Salud Carlos III

Spanish National Centre for Cardiovascular Research

Vall d'Hebron Institut de Recerca

Universitat Autònoma de Barcelona

Ragon Institute of MGH, MIT and Harvard

Centro de Investigación Biomédica en Red

Vall d'Hebron Hospital Universitari

Massachusetts General Hospital

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Antiretroviral therapy duration and immunometabolic state determine efficacy of ex vivo dendritic cell-based treatment restoring functional HIV-specific CD8+ T cells in people living with HIV

EBioMedicine (2022)

Marta Calvet‐Mirabent Ildefonso Sánchez‐Cerrillo Noa B. Martín‐Cófreces Pedro Martínez‐Fleta Hortensia de la Fuente

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated.We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles.HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells.Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants.

Ex vivo

10.1016/j.ebiom.2022.104090

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Citations (16)

Effective innate immune response in natural HIV-1 controllers. Can mimicking lead to novel preventive and cure strategies against HIV-1?

Current Opinion in HIV and AIDS (2022)

Marta Calvet‐Mirabent Enrique Martín‐Gayo

HIV-1 controller individuals represents a model that can be useful for the development of novel vaccines and therapies. Initial studies pointed to the involvement of improved adaptive immunity, however, new emerging evidence suggests the contribution of innate cells to effective antiviral responses in spontaneous controllers. Therefore, understanding the alterations on innate cell subsets might be crucial to develop new effective therapeutic strategies.Among different innate immune cells, dendritic cell (DC) and natural killer (NK) cell are essential for effective antiviral responses. DC from controllers display improved innate detection of HIV-1 transcripts, higher induction of interferons, higher antigen presenting capacities and increased metabolism and higher capacities to induce polyfunctional CD8+ T-cell responses. Such properties have been mimicked by Toll-like receptor ligands and applied to DC-based immunotherapies in humans and in animal models. NK cells from controllers display higher expression of activating receptors promoting increased antibody-dependent cellular cytotoxicity (ADCC) and natural cytotoxicity activities. Neutralizing antibodies in combination with interleukin-15 superagonist or interferon-α can increase ADCC and cytotoxicity in NK cells from HIV-1 progressors.Mimicking DC and NK cell innate profiles in controllers has become a promising strategy to step forward a novel efficient immunotherapy against the HIV-1 infection.

Lead (geology)

10.1097/coh.0000000000000750

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Citations (3)

Author response for "Poly I:C and STING agonist‐primed DC increase lymphoid tissue polyfunctional HIV‐1‐specific CD8 + T cells and limit CD4 + T cell loss in BLT mice"

Marta Calvet‐Mirabent Daniel T. Claiborne Maud Déruaz Serah Tanno Carla Serra

Sting

10.1002/eji.202149502/v2/response1

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MICa/b‐dependent activation of natural killer cells by CD64⁺ inflammatory type 2 dendritic cells contributes to autoimmunity

The EMBO Journal (2023)

Ildefonso Sánchez‐Cerrillo Diego Calzada‐Fraile Ana Triguero‐Martínez Marta Calvet‐Mirabent O. V. Popova

Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56+ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG-I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE-1+ cDC2 and NKG2D+ CD11b+ CD27+ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets.

NKG2D

CD16

10.15252/embj.2023113714

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Citations (6)

NFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins

Nature Communications (2024)

Ilya Tsukalov Ildefonso Sánchez‐Cerrillo Olga Rajas Elena Ávalos Gorane Iturricastillo

Abstract Increased recruitment of transitional and non-classical monocytes in the lung during SARS-CoV-2 infection is associated with COVID-19 severity. However, whether specific innate sensors mediate the activation or differentiation of monocytes in response to different SARS-CoV-2 proteins remain poorly characterized. Here, we show that SARS-CoV-2 Spike 1 but not nucleoprotein induce differentiation of monocytes into transitional or non-classical subsets from both peripheral blood and COVID-19 bronchoalveolar lavage samples in a NFκB-dependent manner, but this process does not require inflammasome activation. However, NLRP3 and NLRC4 differentially regulated CD86 expression in monocytes in response to Spike 1 and Nucleoprotein, respectively. Moreover, monocytes exposed to Spike 1 induce significantly higher proportions of Th1 and Th17 CD4 + T cells. In contrast, monocytes exposed to Nucleoprotein reduce the degranulation of CD8 + T cells from severe COVID-19 patients. Our study provides insights in the differential impact of innate sensors in regulating monocytes in response to different SARS-CoV-2 proteins, which might be useful to better understand COVID-19 immunopathology and identify therapeutic targets.

Monocyte

Nucleoprotein

10.1038/s41467-024-46322-8

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Citations (6)

Antiviral State of CD1c+ cDC contributes to Increased Maturation and Activation of Cytotoxic Natural Killer cells in Sjögren’s Syndrome

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Ildefonso Sánchez‐Cerrillo Marta Calvet‐Mirabent Ana Triguero‐Martínez Diego Calzada‐Fraile Cristina Delgado‐Arévalo

ABSTRACT Objective Primary Sjögren’s syndrome (pSS) is an inflammatory autoimmune disorder characterized by damage of exocrine glands and linked to IFN responses and the induction of autoreactive adaptive immune cells. However, the role of innate immune cells in pSS pathology remains understudied. Methods We studied differential phenotypical characteristics of different NK cell, conventional dendritic cell (cDC) and monocyte subsets in the blood and salivary glands from pSS individuals. Transcriptional patterns of circulating cDC and Mo from pSS and healthy controls were also compared. Finally, in vivo alterations in these cell populations in the salivary gland were investigated in a mouse model. Results Here, we identified CD16+ CD56hi NK cells enriched in pSS patients which associates with higher natural cytotoxic function and increased proportions of circulating CD64+ CD1c+ cDC exhibiting antiviral transcriptional IFN signatures. CD64hi cDC and NK cell were detected infiltrated into the salivary glands from pSS patients and a murine SS model. CD1c+ cDC from patients with pSS expressed high levels of ligands for activating NK receptors and increased ability to activate NK cells ex vivo . Finally, the antiviral RIG-I and DDX60 sensors regulated the expression of NK cell receptor ligands on CD1c+ cDC. Conclusions Therefore, the interplay of CD1c+ cDCs and NK cells could contribute to pSS pathology.

CD16

Ex vivo

10.1101/2022.03.13.484063

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Cooperation between cGAS and RIG-I sensing pathways enables improved innate recognition of HIV-1 by myeloid dendritic cells in elite controllers

Frontiers in Immunology (2022)

Enrique Martín‐Gayo Ce Gao Marta Calvet‐Mirabent Zhengyu Ouyang Mathias Lichterfeld

Spontaneous control of HIV-1 replication in the absence of anti-retroviral therapy (ART) naturally occurs in a small proportion of HIV-1-infected individuals known as elite controllers (EC), likely as a result of improved innate and adaptive immune mechanisms. Previous studies suggest that enhanced cytosolic immune recognition of HIV-1 reverse transcripts in conventional dendritic cells (mDC) from EC enables effective induction of antiviral effector T cell responses. However, the specific molecular circuits responsible for such improved innate recognition of HIV-1 in mDC from these individuals remain unknown.

10.3389/fimmu.2022.1017164

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Citations (6)

ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in PLWH

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Marta Calvet‐Mirabent Ildefonso Sánchez‐Cerrillo Noa B. Martín‐Cófreces Hortensia de la Fuente Ilya Tsukalov

ABSTRACT Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro . In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1-cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.

TIGIT

10.1101/2022.01.14.476403

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POS0367 NLRC4 AND FC-γ-R CROSSTALK ON CD1C+ DENDRITIC CELLS DIFFERENTIALLY CONTRIBUTES TO RHEUMATOID ARTHRITIS IMMUNOPATHOLOGY

Annals of the Rheumatic Diseases (2021)

Cristina Delgado‐Arévalo Marta Calvet‐Mirabent Ana Triguero‐Martínez Enrique Vázquez A. Benguría-Filippini

Background: Rheumatoid arthritis (RA) is an autoimmune disorder in which Th17 cells, B cells and inflammatory cytokines (1-3) contribute to joint tissue damage, however the role of specific myeloid populations to immunopathogenesis of RA remains unclear. Objectives: To address this question, we studied transcriptional, phenotypical and functional characteristics of monocytes (Mo), CD1c + and CD141 + conventional dendritic cells (cDC) from RA patients. Methods: Frequencies and maturation patterns of Lin-CD14-HLADR+ plasmacytoid (CD11c-), CD1c+ and CD141+ cDC (CD11c+) subsets and CD14+ Mo from n=25 RA patients at baseline were analyzed by multicolor flow cytometry. In addition, longitudinal studies on the evolution of these populations after treatment initiation were conducted on a smaller group of RA patients. Moreover, CD1c+ and CD141+ cDC subsets and total Mo were sorted from the peripheral blood from n=4 untreated RA and healthy individuals and the synovial fluid from n=3 RA and chondrocalcinosis patients. Differential transcriptional patterns within each population were analyzed by RNAseq. Functional validation of targets were performed in vitro with cDC subsets isolated form the synoviual fluid of RA patients. Finally, silencing of expression of NLRC4 and NLRP3 on CD1c+cDCs was performed with specific siRNAs. Results: Both CD1c + (p=0.0001) and CD141 + (p=0.0008) cDCs were significantly depleted from the blood and enriched in the synovial fluid from untreated RA patients, but proportions of CD1c+ cDCs were more significantly recovered after treatment initiation and associated with improved clinical parameters. In addition, specific increased expression levels of the IgG-Fc receptor CD64 on CD1c + cDC was associated with higher DAS28 (p=0.0002). Moreover, differential transcriptional patterns of circulating CD1c + cDCs from RA patients were characterized by genes linked to toll-like receptor, Fc-receptor, inflammasome pathways and elevated CCR2 expression (p=0.016), while CD141 + cDCs transcribed interferon-related genes. Importantly, CCR2 + CD64 Hi CD1c + cDCs from the synovial fluid from RA patients transcribed proinflammatory cytokines such as IL1-β, CCL3 and IL-8, actively expressed the inflammasome mediator caspase 1 and were more effective activating pathogenic IFNγ + IL-17 + CD4 + T cells in vitro than CD141 + cDC (p=0.0019). These functional profiles could be artificially induced stimulating CD1c + cDCs with dsDNA in the presence of IgGs and was dependent on caspase 1 and the NLRC4 inflammasome. Conclusion: Our data provides novel insights about specific activation and functional patterns on CD1c + cDC contributing to RA pathogenesis and identifies new sensors that could represent novel therapeutic target to treat RA. References: [1]Alvandpur N, Tabatabaei R, Tahamoli-Roudsari A, Basiri Z, Behzad M, Rezaeepoor M, et al. Circulating IFN-gamma producing CD4+ T cells and IL-17A producing CD4+ T cells, HLA-shared epitope and ACPA may characterize the clinical response to therapy in rheumatoid arthritis patients. Human immunology. 2020. [2]Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(33):14751-6. [3]Chapuy-Regaud S, Nogueira L, Clavel C, Sebbag M, Vincent C, Serre G. IgG subclass distribution of the rheumatoid arthritis-specific autoantibodies to citrullinated fibrin. Clinical and experimental immunology. 2005;139(3):542-50. Disclosure of Interests: None declared

CD11c

CD64

10.1136/annrheumdis-2021-eular.3192

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PP7.1-00174 Active HIV reservoir in jejunum exhibit distinct phenotypic features and evoke innate cell redistribution

Journal of Virus Eradication (2024)

Marta Calvet‐Mirabent M. Yuan Xiaoyu Luo Julie Frouard Jason Neidleman

Redistribution

Jejunum

10.1016/j.jve.2024.100524

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