Biology subjects

Papadopoulou, M.

Publications and source records attributed to Papadopoulou, M..

7 recordsLinked to original sources

bioRxiv2025

γδ T cells are the prime anti-tumoral T cells in pediatric neuroblastoma

High-risk pediatric neuroblastoma patients have a dismal survival rate despite intensive treatment regimens. New treatment options are thus required. Even though HLA expression in neuroblastoma is low and immune cell infiltrates are limited, the presence of tumor infiltrating lymphocytes (TILs) is indicative for better patient survival. Here, we show that most tumor lesions contain viable immune cell infiltrates after induction chemotherapy, with high percentages of CD3+ T cells. We therefore expanded the TILs and tested their anti-tumoral activity. With sufficient starting material, TIL expansion was as efficient as for adult solid tumors. However, whereas TIL products from adult tumors almost exclusively contained {beta} T cells, in neuroblastoma-derived TILs, {gamma}{delta} T cells expanded with similar efficacy as {beta} T cells. Importantly, the anti-tumor responses in response to autologous tumor digest primarily originated from (V{delta}1- and V{delta}3-expressing) {gamma}{delta} T cells, and not from {beta} T cells. In conclusion, this finding creates a window of opportunity for immunotherapy for neuroblastoma patients, with {gamma}{delta} T cells as potential prime responders.

cancer biology↗

bioRxiv2024

Starling murmurations under predation

Large flocks of European starlings change shape, size, and internal structure continuously and rapidly when hunted by aerial predators. How their diverse patterns of collective escape emerge is still unknown. Here, we disentangle the collective behavior of starlings combining video footage of flocks pursued by a robotic predator and a data-driven 3-dimentional agent-based model. In vivo, we show that flock members often differ in their evasive maneuvers and that several collective patterns arise simultaneously across a flock. In silica, we identify individual-level rules that lead to dynamics of collective motion and escape similar to real starlings. Our results suggest that the mechanisms underlying starling murmurations depend on how fast escape information propagates through the flock, the relative positions of the escaping individuals to the predator, and the previous state of the flock (hysteresis). Our study highlights the importance of investigating fine-scale dynamics and micro-macro feedback when studying self-organized adaptive systems.

animal behavior and cognition↗

bioRxiv2023

An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumor Development

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment, serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy; yet, the precise mechanisms via which CAFs imprint on the anti-tumor immunity remain poorly understood. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumor-infiltrating immune cells, which may shape tumor immune evasion. Herein, we describe a synapse formation between -SMA+ CAFs and regulatory T cells (Tregs) in the TME. Foxp3+ Tregs were localized close to -SMA+ CAFs in diverse types of tumor models as well as biopsies from melanoma and colorectal cancer patients. Notably, phenotypically tolerogenic -SMA+ CAFs demonstrated the ability to phagocytose and process tumor antigens, instructing Treg movement arrest, activation and proliferation, in an antigen-specific manner. Of interest, -SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in -SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in -SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg infiltration, attenuated tumor development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between -SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer. One Sentence Summary-SMA+ Cancer Associated Fibroblasts process and present tumor antigens via autophagy to form immunological synapses with Foxp3+ T regulatory cells in the tumor microenvironment, promoting tumor development.

cancer biology↗

bioRxiv2022

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection

The involvement of {gamma}{delta} TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. {gamma}{delta} T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of {beta} T cell deficient mice in order to analyze the memory potential of {gamma}{delta} T cells. As for CMV-specific {beta} T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ {gamma}{delta} TEM that principally localized in infected organ vasculature. Typifying T cell memory, {gamma}{delta} T cell expansion/proliferation in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection involved the T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR {delta} chain repertoire as evidenced by next generation sequencing. The {gamma}{delta} T cell secondary response to MCMV was composed by a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, Long-term-primed {gamma}{delta} TCM cells, but not {gamma}{delta} TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. Overall, our study uncovered memory properties of long-lived TCM {gamma}{delta} T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches. AUTHOR SUMMARYCytomegalovirus (CMV) is a widespread, latent virus that can cause severe organ disease in immune-compromised patients. Anti-CMV memory immune responses are essential to control viral reactivation and/or reinfection events that commonly take place in solid organ transplantation. The role of {gamma}{delta} T-cell receptor bearing lymphocytes could be crucial in this context where immunosuppressive/ablative treatments cause suboptimal and/or delayed {beta} T cell responses. Here we asked whether {gamma}{delta} T cells could compensate for the absence of {beta} T cells in the long-term control of mouse CMV infection. Three months post-primary viral challenge in {beta}-T cell deficient mice, {gamma}{delta} T cells displayed similar features as cytolytic, CMV-specific {beta} CD8 T cells. We showed that previous priming with CMV endowed {gamma}{delta} T cells with an enhanced antiviral potential and that long-term maintenance of {gamma}{delta}-mediated antiviral protection was dependent on {gamma}{delta} central memory T cells (TCM). The {gamma}{delta} T cell response to a secondary CMV challenge was dependent on {gamma}{delta} TCR-signaling and generated a private TCR {delta} repertoire as observed in human. Our results sustain the adaptive-like properties of these unconventional T cells and reveal the interest of targeting {gamma}{delta} TCM subset in novel antiviral vaccination approaches.

immunology↗

bioRxiv2021

Self-organization of collective escape in pigeon flocks

Bird flocks under predation demonstrate complex patterns of collective escape. These patterns may emerge by self-organization from simple interactions among group-members. Computational models have been shown to be valuable for identifying the behavioral rules that may govern these interactions among individuals during collective motion. However, our knowledge of such rules for collective escape is limited by the lack of quantitative data on bird flocks under predation in the field. In the present study, we analyze the first dataset of GPS trajectories of pigeons in airborne flocks attacked by a robotic falcon in order to build a species-specific model of collective escape. We use our model to examine a recently identified distance-dependent pattern of collective behavior that shows an increase in the escape frequency of pigeons when the predator is closer. We first extract from the empirical data the characteristics of pigeon flocks regarding their shape and internal structure (bearing angle and distance to nearest neighbours). Combining these with information on their coordination from the literature, we build an agent-based model tuned to pigeons collective escape. We show that the pattern of increased escape frequency closer to the predator arises without flock-members prioritizing escape when the predator is near. Instead, it emerges through self-organization from an individual rule of predator-avoidance that is independent of predator-prey distance. During this self-organization process, we uncover a role of hysteresis and show that flock members increase their consensus over the escape direction and turn collectively as the predator gets closer. Our results suggest that coordination among flock-members, combined with simple escape rules, reduces the cognitive costs of tracking the predator. Such rules that are independent of predator-prey distance can now be examined in other species. Finally, we emphasize on the important role of computational models in the interpretation of empirical findings of collective behavior. Author summaryBird flocks show fascinating patterns of collective motion, particularly when escaping a predator. Little is however known about their underlying mechanisms. We fill this gap by firstly analyzing GPS data of pigeon flocks under attack by a robotic-predator and secondly, studying their collective escape in a computer simulation. Previous research on pigeons has revealed that flock-members turn away from the predator more the closer the predator gets. Using computer simulations that are based on pigeon-specific characteristics of motion and coordination among individuals, we study what escape rules at the individual level may underlie this distance-dependent pattern. We show that even if individuals do not intend to escape more when the predator is closer, their escape frequency still increases the closer they get to the predator. This happens by self-organization from the coordination among individuals and despite their tendency to turn away from the predator being constant. A key aspect of this process is the increasing consensus among flock members over the escape direction when the predator gets closer.

animal behavior and cognition↗

bioRxiv2019

Intertwined trade-offs coordinate Drosophila midgut mitosis vs. endoreplication and host defense vs. dysplasia

Inflammatory signaling supports host defense against infection, not only through immune cells, but also via regeneration of damaged tissue. Heightened regeneration, nevertheless, predisposes for all types of cancer and thus a trade-off exists between regeneration capacity and long-term tissue homeostasis. Here, we study the role of tissue-intrinsic regenerative inflammatory signaling in stem cell mitosis of the adult Drosophila midgut at the baseline and the infected state and its impact on intestinal host defense to infection and stem cell-mediated dysplasia. Through a quantitative genetics screen we find that stem cell mitosis is positively linked with the expression of eiger, Delta, upd3 and vein in the midgut, as well as with dysplasia and host defense, but negatively with enterocyte endoreplication. We provide evidence that intertwined trade-offs fine-tune midgut homeostasis, according to which stem cell mitosis through cyclin E in stem cells promotes the optimal host defense to infection, unless dysplasia ensues. However, cyclin E in enteroblasts promotes enterocyte endoreplication and counterbalances stem cell mitosis and dysplasia, providing an alternative but less efficient mechanism to support host defense.

cell biology↗

bioRxiv2017

NMDA-receptor antibodies alter cortical microcircuit dynamics

NMDA-receptor antibodies (NMDAR-Ab) cause an autoimmune encephalitis with a diverse range of electroencephalographic (EEG) abnormalities. NMDAR-Ab are believed to disrupt receptor function, but how blocking this excitatory neurotransmitter can lead to paroxysmal EEG abnormalities - or even seizures - is poorly understood. Here, we show that NMDAR-Ab change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity, and predispose to paroxysmal EEG abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in paediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab- related changes render microcircuitry critically susceptible to overt EEG paroxysms, when these key parameters are changed. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.

neuroscience↗