Noa B. Martín‐Cófreces

Universidad Autónoma de Madrid

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Francisco Sánchez‐Madrid

Universidad Autónoma de Madrid

Jesús Vázquez

Spanish National Centre for Cardiovascular Research

ÁG

Álvaro Gómez-Morón

Hospital Universitario de La Princesa

Marta Lozano-Prieto

Hospital Universitario de La Princesa

Enrique Calvo

Spanish National Centre for Cardiovascular Research

Pedro Roda‐Navarro

Research Institute Hospital 12 de Octubre

Marı́a Mittelbrunn

Universidad Autónoma de Madrid

Silvia Requena

Higher University of San Andrés

Camila Scagnetti

Hospital Universitario de La Princesa

Balbino Alarcón

Centro de Biología Molecular Severo Ochoa

Cooperative Institutions

Universidad Autónoma de Madrid

153

Hospital Universitario de La Princesa

Instituto de Salud Carlos III

Consejo Superior de Investigaciones Científicas

Spanish National Centre for Cardiovascular Research

Centro de Investigación Biomédica en Red

Universidad Complutense de Madrid

Centro de Biología Molecular Severo Ochoa

Centro Nacional de Biotecnología

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

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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)

Analysis of Microtubules and Microtubule-Organizing Center at the Immune Synapse

Methods in molecular biology (2017)

Noelia Blas‐Rus Eugenio Bustos‐Morán Francisco Sánchez‐Madrid Noa B. Martín‐Cófreces

Microtubule organizing center

Immunological synapse

Organelle

Cell polarity

Crosstalk

10.1007/978-1-4939-6881-7_3

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Citations (11)

HDAC6 is a Regulator of CTL Function through Control of Lytic Granule Dynamics

Single Cell Biology (2016)

N. Núñez‐Andrade Francisco Sánchez‐Madrid Noa B. Martín‐Cófreces

Viral infections involve specific stress exposure that can influence the quality and average lifespan of an organism.The immune system acts through virus clearance from the organism.Many aspects of immune cells accounting for this response are still under study.Here, we review recent aspects of the molecular mechanisms involved in the delivery of the lethal hit by Cytotoxic T lymphocytes.

Lytic cycle

CTL*

10.4172/2168-9431.1000143

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Citations (2)

Corrigendum: Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8+ T lymphocytes

Frontiers in Immunology (2024)

Álvaro Gómez-Morón Ilya Tsukalov Camila Scagnetti Clara Pertusa Marta Lozano-Prieto

[This corrects the article DOI: 10.3389/fimmu.2024.1411957.].

10.3389/fimmu.2024.1500666

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Editorial: Cytoskeleton Dynamics as Master Regulator of Organelle Reorganization and Intracellular Signaling for Cell-Cell Competition

Frontiers in Cell and Developmental Biology (2021)

Noa B. Martín‐Cófreces Francisco Sánchez‐Madrid Pedro Roda‐Navarro

EDITORIAL article Front. Cell Dev. Biol., 28 October 2021Sec. Cell Adhesion and Migration https://doi.org/10.3389/fcell.2021.782559

Organelle

Master regulator

Cell Signaling

10.3389/fcell.2021.782559

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Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8+ T lymphocytes

Frontiers in Immunology (2024)

Álvaro Gómez-Morón Ilya Tsukalov Camila Scagnetti Clara Pertusa Marta Lozano-Prieto

Introduction CD8 + cytotoxic T lymphocytes (CTLs) are highly effective in defending against viral infections and tumours. They are activated through the recognition of peptide–MHC-I complex by the T-cell receptor (TCR) and co-stimulation. This cognate interaction promotes the organisation of intimate cell–cell connections that involve cytoskeleton rearrangement to enable effector function and clearance of the target cell. This is key for the asymmetric transport and mobilisation of lytic granules to the cell–cell contact, promoting directed secretion of lytic mediators such as granzymes and perforin. Mitochondria play a role in regulating CTL function by controlling processes such as calcium flux, providing the necessary energy through oxidative phosphorylation, and its own protein translation on 55S ribosomes. However, the effect of acute inhibition of cytosolic translation in the rapid response after TCR has not been studied in mature CTLs. Methods Here, we investigated the importance of cytosolic protein synthesis in human CTLs after early TCR activation and CD28 co-stimulation for the dynamic reorganisation of the cytoskeleton, mitochondria, and lytic granules through short-term chemical inhibition of 80S ribosomes by cycloheximide and 80S and 55S by puromycin. Results We observed that eukaryotic ribosome function is required to allow proper asymmetric reorganisation of the tubulin cytoskeleton and mitochondria and mTOR pathway activation early upon TCR activation in human primary CTLs. Discussion Cytosolic protein translation is required to increase glucose metabolism and degranulation capacity upon TCR activation and thus to regulate the full effector function of human CTLs.

Granzyme

10.3389/fimmu.2024.1411957

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Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor

The Journal of Immunology (2009)

Bárbara Acosta‐Iborra Ainara Elorza Isabel M. Olazabal Noa B. Martín‐Cófreces Silvia Martı́n-Puig

Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-gamma and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-gamma increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-gamma induction was mediated through HIF-1alpha binding to its promoter on a new functional hypoxia response element. The requirement of HIF-alpha in the IFN-gamma induction was confirmed in RAW264.7 cells, where HIF-1alpha was knocked down, as well as in resident HIF-1alpha null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3epsilon, CD3zeta and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1alpha- and in IFN-gamma-silenced macrophages, indicating a link between HIF-1alpha and IFN-gamma in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1alpha-mediated increase in IFN-gamma levels.

Hypoxia

10.4049/jimmunol.0801710

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Citations (93)

Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells

Nature Communications (2023)

Diego Calzada‐Fraile Salvador Iborra Marta Ramírez‐Huesca Inmaculada Jorge Enrico Dotta

Abstract Antigen cognate dendritic cell (DC)-T cell synaptic interactions drive activation of T cells and instruct DCs. Upon receiving CD4 + T cell help, post-synaptic DCs (psDCs) are licensed to generate CD8 + T cell responses. However, the cellular and molecular mechanisms that enable psDCs licensing remain unclear. Here, we describe that antigen presentation induces an upregulation of MHC-I protein molecules and increased lipid peroxidation on psDCs in vitro and in vivo. We also show that these events mediate DC licensing. In addition, psDC adoptive transfer enhances pathogen-specific CD8 + T responses and protects mice from infection in a CD8 + T cell-dependent manner. Conversely, depletion of psDCs in vivo abrogates antigen-specific CD8 + T cell responses during immunization. Together, our data show that psDCs enable CD8 + T cell responses in vivo during vaccination and reveal crucial molecular events underlying psDC licensing.

Priming (agriculture)

Immunological synapse

10.1038/s41467-023-42480-3

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Citations (7)

bFGF Stimulates GAP-43 Phosphorylation at Ser41 and Modifies Its Intracellular Localization in Cultured Hippocampal Neurons

Molecular and Cellular Neuroscience (2000)

Pedro Tejero-Dı́ez Paloma Rodrı́guez-Sánchez Noa B. Martín‐Cófreces F. Javier Dı́ez-Guerra

Cell fractionation

Gap-43 protein

10.1006/mcne.2000.0915

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Citations (33)

Post-translational modifications and stabilization of microtubules regulate transport of viral factors during infections

Biochemical Society Transactions (2021)

Silvia Requena Francisco Sánchez‐Madrid Noa B. Martín‐Cófreces

Tubulin post-translational modifications (PTMs) constitute a source of diversity for microtubule (MT) functions, in addition to the different isotypes of α and β-tubulin acting as building blocks of MTs. Also, MT-associated proteins (MAPs) confer different characteristics to MTs. The combination of all these factors regulates the stability of these structures that act as rails to transport organelles within the cell, facilitating the association of motor complexes. All these functions are involved in crucial cellular processes in most cell types, ranging from spindle formation in mitosis to the defense against incoming cellular threats during phagocytosis mediated by immune cells. The regulation of MT dynamics through tubulin PTMs has evolved to depend on many different factors that act in a complex orchestrated manner. These tightly regulated processes are particularly relevant during the induction of effective immune responses against pathogens. Viruses have proved not only to hijack MTs and MAPs in order to favor an efficient infection, but also to induce certain PTMs that improve their cellular spread and lead to secondary consequences of viral processes. In this review, we offer a perspective on relevant MT-related elements exploited by viruses.

Organelle

10.1042/bst20210017

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Citations (6)