1,721,033 research outputs found
Benefit of circadian clocks in adaptive immunity and vaccination responses
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Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy
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The sympathetic nervous system and natural killer cell activity in rhythmic anti-tumor immune responses
No full textCircadian rhythms are evolutionarily conserved mechanisms that exist in almost all organisms. They integrate environmental changes with internal physiology, allowing the synchronization of physiological mechanisms and behavior. In mammals, circadian rhythms are generated in the suprachiasmatic nucleus of the hypothalamus, which in turn distributes synchronization signals to the rest of the body via humoral cues and peripheral innervation. In the context of immunity, the peripheral nervous system, particularly the sympathetic nervous system, has been shown to control the circadian function of leukocytes, making this axis a potential target for the regulation of circadian immunity in a number of pathological conditions. For instance, previous studies from our lab and others showed that diurnal oscillations in leukocyte composition and distribution control the growth profile of tumors. However, whether sympathetic inputs are involved in the diurnal leukocyte composition of the tumor microenvironment and whether the sympathetic nervous system is involved in rhythmic anti-tumor activities remains unknown. In my PhD thesis, I aim to demonstrate the connection between the peripheral nervous system and the immune system, particularly in tumor progression.
In the first part of this thesis, I investigate how chemical and genetic denervation affects the rhythmicity of tumor growth. Interestingly, I demonstrate that genetic deletion of beta-2 adrenergic signaling reverses the time-of-day dependent tumor growth pattern. The abundance of tumor-infiltrating leukocytes correlates with this inverted tumor growth phenotype. Interestingly, by flow cytometry analysis of infiltrating leukocytes in wild-type in comparison with Adrb2 KO, I show that natural killer cells are one of the major leukocyte subsets affected, and their distribution correlate with the inversion pattern of tumor growth at later stages. Furthermore, I show that the inversion of tumor growth after depletion of NK cells in wild-type mice is comparable to the inversions in mice deficient in beta-2 adrenergic signaling. In addition, NK cells show oscillations in clock genes and cytotoxicity after synchronization ex vivo. Together, these data show that adrenergic signaling in NK cells is important for controlling tumor growth in a time-dependent manner and advocate for improved immunotherapies such as combinatorial therapies using adrenergic signaling modulators or CAR-NK cells.
In the second part of the thesis, I focus on imaging tumor-associated neuro-immune interactions using confocal microscopy in different murine tumor models. Specifically, I show the presence of sympathetic nerve fibers in the T-cell zone of lymph nodes in wild-type mice. Additionally, in a mouse model of a bladder tumor, I show a reduction in TReg cells at the primary bladder tumor site, where the tissue is rich in sensory innervation. These studies highlight the importance of understanding neuro-immune interactions both in lymphoid organs and in the tumor microenvironment to provide insight into neuro-immune control of tumor growth ultimately resulting in novel and/or improved therapeutic approaches.</p
Time-of-day effect on adaptive immune responses and central nervous system autoimmunity
No full textCircadian rhythms are present in virtually all organisms and are evolutionarily conserved time-keeping mechanisms describing biological processes that oscillate in approximately 24-hour patterns. These rhythms are kept in synchrony by environmental cues and participate in the proper function of several physiological processes, among which are the innate and the adaptive immune system. Circadian rhythms are beneficial as they allow organisms to anticipate recurring events and to tune their behavioral response accordingly. With respect to immunity, these rhythms help the host to modulate its reactivity to times at which the probability of pathogen encounters may be highest. In addition, time-of-day-dependent activation of the immune system must be tightly controlled to trigger an efficient immune response without inducing side effects such as autoimmunity.
It is now widely accepted that time-of-day-dependent mechanisms can govern an acute immune response. However, we still do not understand why adaptive immune responses remain oscillatory over long periods of time. In the first part of this thesis, I demonstrate that the initial time of the challenge is key to shape the adaptive immune response for the ensuing several weeks. In particular, the time-of-day-dependent migration of dendritic cells generates oscillations in lymph node cellularity, which persists for weeks after the initial challenge and results in an increased likelihood of functional encounters between antigen-presenting dendritic cells and antigen-recognizing T cells. This is especially important in the context of immune responses to vaccination. Additionally, I show that rhythmic migration, activation, and function of different immune cells are required to create and maintain an efficient immune response over time.
However, immune responses are not always beneficial as is the case for an immune response directed against self, which can lead to autoimmunity. The second part of the thesis aims to decipher to what extent circadian rhythms are contributing to the development of experimental autoimmune encephalomyelitis (EAE), the most common mouse model of multiple sclerosis (MS). Using this model, I show a time-of-day dependent infiltration of immune cells into the central nervous system (CNS) during EAE development that is independent of disease severity. Interestingly, I observe a substantial increase in blood circulating CD11b+Ly6G+ cells before the appearance of symptoms associated with a switch in their phenotype. Altogether, these data suggest a potential contribution of CD11b+Ly6G+ leukocytes to early disease. Analysis of the mRNA levels in the spinal cord of EAE animals reveal a time-of-day dependent expression of both Cxcl1 and Cxcl2 chemokines responsible for the migration of monocytes and neutrophils, respectively. This study suggests the importance of circadian oscillations in cell infiltration in the central nervous system, as well as the importance of CD11b+Ly6G+ leukocytes in EAE development and identifies these cells as potential early biomarkers for diagnosis purposes and new therapeutic targets in MS patients.</p
Circadian control of anti-tumor immune responses
No full textCircadian rhythms are a feature common to most physiological processes. These rhythms in the body are synchronized to the environment by external cues. Studies have shown that the initial time of day when an organism encounters an inflammatory stimulus determines the strength of the subsequent immune response. This phenomenon is true for both the innate and the adaptive immune system. Despite what is known about rhythmic immunity at steady state and during an acute inflammation, it is still unknown how circadian rhythms affect the influence of the immune system to cancer. The process of cancer immunosurveillance is a mechanism of tumor suppression that can protect the host from cancer development throughout its lifetime. Yet, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over the course of a single day.
Here, I demonstrate that the initial time-of-day of tumor engraftment dictates the ensuing tumor growth across murine cancer models. Using immunocompromised NSG as well as Rag2 knock-out mice, I could trace this difference to the adaptive immune system. By using a series of antibodies to deplete subpopulations of immune cells, I found dendritic cells (DCs) and CD8 T cells to be the major effector cells in the control of the diurnal tumor growth. More specifically, rhythmicity in the anti-tumor response was abrogated in mice exhibiting lineage-specific loss of circadian rhythmicity in DCs or T cells by deletion of the circadian gene Bmal1. I found that rhythmic trafficking of DCs to the tumor draining lymph node (dLN) governs a circadian response of tumor antigen-specific CD8+ T cells. This is dependent on an oscillation in the number and function of DCs. Mechanistically, DCs exhibit a cell-intrinsic circadian expression of the co-stimulatory molecule CD80. Chromatin immunoprecipitation revealed rhythmic binding of BMAL1 to the promoter region of Cd80, indicating a direct control of Cd80 expression by BMAL1 and the circadian clock.
Adjusting the administration time of anti-tumor vaccination enhanced the efficacy in controlling tumor growth, a phenomenon dependent on the DC-intrinsic clock. Administering the vaccine during the day promoted higher levels of antigen-bearing DCs in the draining lymph node, as well as more antigen-specific T cells, compared to night-time vaccination. Additionally, human monocyte derived DCs also presented time-of-day oscillations in CD80, resulting in oscillatory CD8 T cell proliferation.
Consequently, cancer immunotherapy was demonstrated to be more effective when synchronized with rhythmic trafficking of DCs from the tumor to the draining lymph node, as well as peak CD80 expression on DCs, resulting in better CD8 proliferation in mice. In humans, retrospective data also showed a time-of-day dependency for tumor vaccination with respect to the generation of melanoma antigen-specific T cells. These data demonstrate that circadian rhythms of anti-tumor immune components are not only critical for the control of tumor growth, but might also be used to enhance existing therapeutic cancer treatments.
Les rythmes circadiens sont une caractéristique commune à la plupart des processus physiologiques. Dans l’organisme, ces rythmes sont synchronisés avec l'environnement par des signaux externes. Des études ont montré que le moment initial de la journée auquel un organisme rencontre un stimulus inflammatoire détermine la puissance de la réponse immunitaire ultérieure. Ceci s’applique autant au système immunitaire inné qu’au système immunitaire adaptatif. Malgré ce que l'on sait de la rythmicité de l'immunité à l'état d’équilibre et pendant une inflammation aiguë, on ne connait toujours pas comment les rythmes circadiens affectent l'influence du système immunitaire sur le cancer. Le processus d'immunosurveillance du cancer est un mécanisme de suppression des tumeurs qui permet de protéger l'hôte du développement de cancers tout au long de sa vie. Cependant, on ignore si l'efficacité de l'immunosurveillance du cancer fluctue au cours de la journée.
Je démontre ici que le temps initial de la greffe tumorale détermine la croissance tumorale qui s'ensuit dans plusieurs modèles murins de cancer. En utilisant des souris NSG immunodéprimées ainsi que des souris Rag2 knock-out, j'ai pu établir la relation entre cette différence et le système immunitaire adaptatif. En utilisant une série d'anticorps pour appauvrir certaines sous-populations de cellules immunitaires, j'ai découvert que les cellules dendritiques et les cellules T CD8+ étaient les principales cellules effectrices dans le contrôle de la croissance diurne des tumeurs. Plus précisément, la rythmicité de la réponse anti-tumorale était abrogée chez les souris présentant une perte de la rythmicité circadienne, par délétion du gène circadien Bmal1, dans les cellules dendritiques ou les cellules T. J'ai découvert que le trafic rythmique des cellules dendritiques vers le ganglion lymphatique drainant de la tumeur régit une réponse circadienne des cellules T CD8+ spécifiques de l'antigène de la tumeur. Cette réponse dépend de l’oscillation du nombre et de la fonction des cellules dendritiques. D'un point de vue mécanistique, les cellules dendritiques présentent une expression circadienne intrinsèque de la molécule co-stimulatrice CD80. Par immunoprécipitation de la chromatine (ChIP), nous avons révélé une liaison rythmique de BMAL1 à la région promotrice du gène Cd80, indiquant un contrôle direct de l'expression de Cd80 par BMAL1 et l'horloge circadienne.
L'ajustement du moment d'administration de la vaccination antitumorale a permis d’améliorer l'efficacité du contrôle de la croissance tumorale, un phénomène dépendant de l'horloge intrinsèque des cellules dendritiques. L'administration du vaccin pendant la journée augmente le nombre de cellules dendritiques porteuses d'antigènes dans le ganglion lymphatique drainant, ainsi que le nombre de cellules T spécifiques de l'antigène, par rapport à la vaccination de nuit. De plus, les cellules dendritiques dérivées de monocytes humains présentaient également des oscillations du CD80 en fonction du moment de la journée, ce qui a résulté en une prolifération oscillatoire des cellules T CD8+.
Par conséquent, il a été démontré que l'immunothérapie contre le cancer était plus efficace lorsqu'elle était synchronisée avec le trafic rythmique des cellules dendritiques de la tumeur vers le ganglion lymphatique drainant, ainsi qu'avec le pic d'expression du</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Control of dendritic cell dynamics in the skin by the sympathetic nervous system
No full textThe connection between the nervous and immune systems is increasingly recognized as crucial for health and disease. Specifically, the sympathetic nervous system (SNS) has been shown to strongly impact immune responses. SNS fibers innervate all tissues and release the catecholamine noradrenaline locally. Highly diverse cell types respond to noradrenaline through cell surface G-protein coupled a- or b-adrenergic receptors (ARs). The skin represents one of the first lines of defense of an organism against pathogens and it is densely innervated by SNS fibers. It harbors numerous immune cells, among which we find dendritic cells (DCs), that act as sentinels, reacting to pathogens or malignant cell proliferation by mounting a robust inflammatory response and inducing the recruitment of additional immune cells. The migration of DCs through the lymphatic vessels network is crucial to achieve an efficient adaptive immune response. The SNS has been shown to govern immune cell trafficking and the inflammatory response in several peripheral tissues, such as lymph node as well as skeletal muscle, bone marrow and blood. This study investigated how the SNS governs DC trafficking within the skin.
Here, I demonstrated that noradrenergic signaling via b2-AR, the primary receptor for norepinephrine on immune cells, regulates DCs migration towards both skin LVs and skin draining lymph nodes (dLNs). Specifically, mice lacking b2-AR (b2KO), showed increased DC migration towards lymphatic vessels compared to WT mice ex vivo. This phenotype was confirmed via pharmacological inhibition using the specific b2-AR antagonist clenbuterol. Adoptive transfer of bone marrow derived dendritic cells (BMDCs) in the skin showed that the main player involved in this phenomenon in vivo are DCs, as b2KO BMDCs had an advantage in the migration towards skin dLNs, regardless of the genotype of the recipient.
This enhanced migration in b2KO DCs also impacted tumor responses, due to the central role of DCs in orchestrating effective CD8+T cell responses against tumors. B16-OVA melanoma tumor bearing mice vaccinated with b2KO BMDCs, showed a stronger anti-tumor immune response compared to mice vaccinated with WT BMDCs. Importantly, single-cell RNA sequencing analysis of mouse skin revealed that cDC1s are the DCs subpopulation which expresses the highest levels of the b2-AR. Vaccinating B16-OVA melanoma tumor bearing mice with cDC1s lacking noradrenergic signaling (either b2KO cDC1s or WT cDC1s pre-conditioned with the specific b2-AR antagonist ICI.118.551), resulted in a significantly better tumor control, VIIIcompared to control mice. One of the factors driving this effect could be the proximity observed between XCR1+ cDC1s and TH+ sympathetic nerves in the skin.
This study sheds light on how the SNS modulates the immune system and this may lead to the pharmacological optimization of vaccination regimes, as well as anti-tumor therapies.</p
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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