CCR5 Is Essential for NK Cell Trafficking and Host Survival following Toxoplasma gondii Infection

The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5(−/−)) mice were less able to generate an inflammatory response, had decreased chemokine and interferon γ production, and had higher parasite burden. As a result, CCR5(−/−) mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5(+/+) NK cells into CCR5(−/−) mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

"Tolle, lege!" - Didactic reflexion and practical test of "sighted" reading

1\. Einleitende Beobachtungen 6 1.1. Problemfeld Lesen 6 1.2. Lesen im sozio- kulturellen Kontext 11 1.3. Lesen empirisch beobachtet 12 1.4. Formulierung der Fragestellung und des methodischen Aufbaus 15 2\. Lesen und Literaturwissenschaft 17 2.1. Ergebnisse der empirischen Leseforschung 17 2.2. Häppchenlesen 18 2.3. Lesebiographie 21 2.4. Pflicht-lesen 25 3\. Spezifika Philosophischen Lesens 31 3.1. Lesen und Erkennen 36 3.1.1. Literarische Erkenntnis 36 3.1.2. Sehen als Erkennen 40 3.2. Literarische Philosophie und philosophische Literatur 42 3.2.1. Texte für den Philosophieunterricht 45 3.2.2. Zusammenfassung 48 3.3. Lesen im Unterricht als Bewegung des Denkens 50 3.4. Pluralität der Lesemodi 51 3.4.1. Analytisches Lesen 51 3.4.2. Sehendes Lesen 58 3.4.2.1. Philosophie der menschlichen Dinge 59 3.4.2.2. Literarisch- sprachliche Ausformung der Philosophie der menschlichen Dinge 62 3.5. Die Struktur sehenden Lesens 64 3.5.1. Phantasie 65 3.5.2. Sehen 67 4\. Sehendes Lesen bei Friedrich Nietzsche 72 4.1. Lesen und Wiedererkennen 72 4.2. Nietzsche als Leser 84 4.3. Nietzsche lesen 86 4.3.1. Das Wort vom Spiel 88 4.3.2. Leben als Er-Leben 93 4.3.3. Erfahren und Leben 96 4.3.4. Die andere Seite 100 Etymologischer Exkurs: Der Begriff Experiment 106 4.3.5. „Leser, wie ich sie brauche“ 109 4.3.5.1. „Orales“ Lesen oder: Lesen mit Leib und Seele 110 4.3.5.2. Musisches Lesen oder: Lesen mit Geschmack 114 4.3.5.3. Elitäres Lesen 120 4.3.5.4. Ruhe. 122 4.3.5.5. Kriterium. 124 4.3.5.6. Resultate. 126 4.4. Zusammenfassung 130 5\. Stellenwert des Lesens in der Fachdidaktik 131 5.1. Fachdidaktische Impulse aus der Beschäftigung mit F. Nietzsche 131 5.2. Fachdidaktische Ansätze in der Tradition analytischen Lesens 132 Josef Schmucker-Hartmann – Wulff Rehfus – Martin Euringer – Jonas Pfister – Jay F. Rosenberg – Reinhard Brandt – Volker Pfeifer – Barbara Brüning – Johannes Rohbeck - 133 Historischer Exkurs: Die sog. Lesewut im 18. Jh. 152 Volker Steenblock – Van der Leeuw/Mostert 163 5.3. Fachdidaktische Ansätze in der Tradition sehenden Lesens 167 Ekkehard Martens – Christian Gefert - Stephen Law – Jens Soentgen – Olaf Breidbach – Kurt Langebeck 167 5.4. Lesen im Bereich Kompetenzorientierung 184 Anita Rösch 184 5.5. Zusammenfassung und Weiterführung 187 6\. Praktische Erprobung: Der Mindelheimer Philosophiepreis als spezifisch philosophischer Beitrag zur Leseerziehung 195 6.1. Idee und Konzept des Mindelheimer Philosophiepreises 195 6.1.1. Dotierung 200 6.1.2. Zusammenarbeit mit öffentlichen Institutionen, Sponsoren 201 6.1.3. Frankfurter Buchmesse 201 6.1.4. Preisverleihung und philosophisches Cafe 203 6.1.5. Meisterklasse des Mindelheimer Philosophiepreises 203 6.2. Lektürearbeit in der Jury 204 6.2.1. Wahl der Jury und Präsentation 204 6.2.2. Bereitstellung der Leseexemplare in der Schülerbücherei 207 6.2.3. Lesen der eingereichten Bücher 208 6.2.4. regelmäßige Jurysitzungen 212 6.2.5. Präsentation und Repräsentation 218 6.3. Interview mit Jurymitgliedern 220 7\. Resümee 232 Literatur 239Die vorliegende Arbeit geht der Frage nach, ob innerhalb schulischer Leseerziehung von einem eigenen philosophischen Lesemodus ausgegangen werden kann. Ausgangspunkt der Erörterung bilden Ergebnisse empirischer Untersuchungen zur Lesefähigkeit Jugendlicher in der BRD (PISA). Die Vergleichszahlen zeigen, dass eine Veränderung der grundsätzlichen Problematik zwischen 2009 und 2012 nur innerhalb der grundlegenden Stufen der Lesekompetenz stattfindet, nicht aber in den Kompetenzbereichen Interpretation und Beurteilung. Auch innerhalb der Leseforschung der Literaturwissenschaft werden wesentliche Veränderungen sowie Defizite bzgl. Lesefähigkeit und Lesebereitschaft junger Menschen festgestellt. Deshalb muss gefragt werden, welche didaktischen Folgen diese Ergebnisse für das Lesen von Texten im Philosophieunterricht haben. In der Philosophiegeschichte bilden sich zwei Ansätze des Denkens und Erkennens heraus, die sich auf die Bedeutung des Lesens auswirken. Analytisches Lesen ver-steht sich als eine Methode der Texterschließung, die den Text methodisch-exakt analysiert und untersucht. Sehendes Lesen geht von einer subjektiven Begegnung des Lesers mit dem Text aus, die ihn betrifft und in Anspruch nimmt. Sehendes Lesen kann auf eine eigene philosophiegeschichtliche Tradition zurückgeführt werden, die sich in besonderer Weise bei Friedrich Nietzsche darstellen lässt: Nietzsche stellt das Lesen in den Zusammenhang seiner Philosophie, die Leben und Lesen als Experiment versteht. Der Mensch ist vor sich selbst gestellt und in seinem Denken und in seiner Existenz unmittelbar betroffen. Eine Untersuchung des griechischen Verständnisses von Lesen zeigt am Übergang von der Oralität zur Literarität, dass Lesen als Wiedererkennen verstanden wurde. Der Mensch erkennt sich selbst und seine Welt in den Zeichen der Schrift wieder. Analytisches und sehendes Lesen ergänzen einander und tragen dazu bei, dass der Leser in einen Dialog mit dem Text eintritt. Sehendes Lesen als unmittelbarer Textzugang stellt die subjektiven Leseerfahrungen in den Mittelpunkt. Im Vordergrund steht nicht die Form oder Art des Textes, sondern die Tätigkeit des Lesens. Philoso-phisch ist dieser Lesemodus, insofern er den Leser anleitet, nicht nur Fragen an den Text zu stellen, sondern sich selbst und seine Lebensführung in Frage stellen zu lassen. Es geht um die praktische Seite des Lebens. Der Mindelheimer Philosophiepreis versteht sich als Projekt, das sich der eingangs formulierten Frage stellt. Schülerinnen und Schüler verfügen bereits über die Fähigkeit analytischen Lesens und lernen zusätzlich den Modus sehenden Lesens kennen. Über die Methode der Juryarbeit werden folgende Fähigkeiten eingeübt: freiwillige Übernahme von Verantwortung als Leser der eingereichten Bücher, Gespräch und Dialog über persönliche Leseerfahrungen in der Jury, Überprüfung der eigenen Beurteilung in gemeinsamer Auseinandersetzung, Erfahrung von Philosophie als Tätigkeit des Philosophierens. Dialog und Begegnung durch gemeinsames Lesen, das um den Nutzen analytischer Texterschließung weiß und ihre Methodik nutzt, werden im Mindelheimer Philosophiepreis für die Juroren zu einer bereichernden Erfahrung lebendigen Lesens - philosophischen Lesens.The present study examines the question whether in the context of school-based reading instruction there can be a philosophical reading mode of its own. The start-ing point for the discussion consists of the results of empirical studies on the literacy of pupils in Germany (PISA). The comparative figures show that a change in the fundamental issue between 2009 and 2012 takes place only within the basic levels of literacy, but not in the competence areas of interpretation and judgment. Even within the reading research of literary studies major changes and deficits with respect to reading ability and reading readiness of young people are detected. Therefore the didactic consequences of these results for the reading of texts in philos-ophy classes must be discussed. In the history of philosophy two approaches of thinking and cognition have emerged that have an impact on the importance of reading. Analytical reading is understood as being a method of text recovery, which analyses and examines the text in a meth-odologically exact manner. Seeing reading is based on a subjective encounter of the reader with the text, which concerns him and makes demands on the reader. Seeing reading can be traced back to its own tradition of philosophic history, which is represented by Friedrich Nietzsche in a special way: Nietzsche puts reading into the context of his philosophy, understanding life and reading as an experiment. Man is put into confrontation with himself and directly concerned both in his way of thinking and in his existence. A study of the classical Greek understanding of read-ing shows on the transition from orality to literacy that reading was seen as a way of recognition. Man recognizes himself and his world in the signs of scripture again. Analytical and seeing reading complement each other and help the reader to enter into dialogue with the text. With seeing reading offering an immediate access to a text, the subjective reading experiences of the students are put at the center. Thereby it is not the form or nature of the text which is in the focus, but the act of reading it-self. This reading mode is philosophical, so far as it guides the reader not only to ask questions to the text, but to have himself and his own lifestyle called into question. It is the practical side of life that matters. The Mindelheimer Philosophiepreis can be seen as a project that turns to the initially formulated question. Students already have the ability of the analytical mode of reading in addition to learning the reading mode of seeing. Due to the method of jury work the following skills are practiced: voluntary assumption of responsibility as a reader of submitted books, discussion and dialogue on personal reading experi-ence between the members of the jury, a review of one´s own judgment in joint de-bate as well as experience of philosophy as an activity of philosophizing. In Mindelheimer Philosophiepreis dialogue and encounter through shared reading that is aware of the benefits of text analysis and uses its methodology turn for the jurors into an enriching experience of lively reading – of philosophical reading

Downregulated IL-21 Response and T Follicular Helper Cell Exhaustion Correlate with Compromised CD8 T Cell Immunity during Chronic Toxoplasmosis

CD8 T cells are important for maintaining the chronicity of Toxoplasma gondii infection. In a T. gondii encephalitis susceptible model, we recently demonstrated that CD4 T cells play an essential helper role in the maintenance of the effector response and CD8 T cell dysfunctionality was linked to CD4 T cell exhaustion. However, CD4 T cells are constituted of different subsets with various functions and the population(s) providing help to the CD8 T cells has not yet been determined. In the present study, T follicular helper cells (Tfh), which are known to be essential for B cell maturation and are one of the main sources of IL-21, were significantly increased during chronic toxoplasmosis. However, at week 7 p.i., when CD8 T cells are exhausted, the Tfh population exhibited increased expression of several inhibitory receptors and levels of IL-21 in the serum were decreased. The importance of IL-21 in the maintenance of CD8 T cells function after T. gondii infection was further demonstrated in IL-21R KO mouse model. Interestingly, while CD8 T cells from both knockout (KO) and wild-type mice expressed similar levels of PD-1, animals with defective IL-21 signaling exhibited lower polyfunctionality than wild-type controls. This reduced polyfunctional ability observed in CD8 T cells from KO mice was associated with a significant increase in other inhibitory receptors like Tim-3, LAG-3, and 2B4. Furthermore, the animals exhibited greater signs of Toxoplasma reactivation manifested by the reduced number of cysts and increased expression of tachyzoite (replicative form of the parasite) specific genes (SAG1 and ENO2) in the brain. Also, IL-21R KO mice displayed a higher frequency of tachyzoite-infected monocytes in the blood and spleen. Our findings suggest the importance of Tfh and IL-21 during chronic toxoplasmosis and establish a critical role for this cytokine in regulating CD8 T cell dysfunction by preventing the co-expression of multiple inhibitory receptors during chronic parasitic infection

Downregulated IL-21 response and T follicular helper cell exhaustion correlate with compromised CD8 T cell immunity during chronic Toxoplasmosis

CD8 T cells are important for maintaining the chronicity of Toxoplasma gondii infection. In a T. gondii encephalitis susceptible model, we recently demonstrated that CD4 T cells play an essential helper role in the maintenance of the effector response and CD8 T cell dysfunctionality was linked to CD4 T cell exhaustion. However, CD4 T cells are constituted of different subsets with various functions and the population(s) providing help to the CD8 T cells has not yet been determined. In the present study, Tfh cells (T follicular helper), which are known to be essential for B cell maturation and are one of the main sources of IL-21, were significantly increased during chronic toxoplasmosis. However, at week 7 p.i., when CD8 T cells are exhausted, the Tfh population exhibited increased expression of several inhibitory receptors and levels of IL-21 in the serum were decreased. The importance of IL-21 in the maintenance of CD8 T cells function after T. gondii infection was further demonstrated in IL-21R KO mouse model. Interestingly, while CD8 T cells from both knockout and wild type mice expressed similar levels of PD-1, animals with defective IL-21 signaling exhibited lower polyfunctionality than wild type controls. This reduced polyfunctional ability observed in CD8 T cells from knockout mice was associated with a significant increase in other inhibitory receptors like Tim-3, LAG-3 and 2B4. Furthermore, the animals exhibited greater signs of Toxoplasma reactivation manifested by the reduced number of cysts and increased expression of tachyzoite (replicative form of the parasite) specific genes (SAG1 and ENO2) in the brain. Also, knockout mice displayed a higher frequency of tachyzoite infected monocytes in the blood and spleen. Our findings suggest the importance of Tfh and IL-21 during chronic toxoplasmosis and establish a critical role for this cytokine in regulating CD8 T cell dysfunction by preventing the co-expression of multiple inhibitory receptors during chronic parasitic infection

Role of Il-21 in CD8 T cell response against E.cuniculi infection

Microsporidia are a group of obligate intracellular opportunistic parasites that induce a wide-range of pathology in immunocompromised individuals, including HIV-AIDS patients, organ transplant recipients, cancer patients and the elderly. Among the many species of microsporidia, at least eight can infect humans, but the pathogen is often underdiagnosed due to its small size and the need to be identified by specialized staining techniques. Encephalitozoon cuniculi is a microsporidia with one of the widest host ranges among mammals and has the ability to disseminate into multiple tissues. Due to the fact that it can be cultured in the laboratory, a majority of experimental studies have been conducted with E.cuniculi. In a mouse model of E.cuniculi infection, robust CD8 T cell response manifested by strong polyfunctional characteristics (both IFNg and cytolytic activity) is critical for host protection. Interestingly, the parasite does not induce a high inflammatory environment, and the CD8 T cell response elicited after oral/natural infection is independent of IL-2 and primarily driven by IL-21. Although importance of IL-21 is associated with B cell responses, this cytokine has also been reported to play a critical role in maintaining a robust CD8 T cell memory. We observed that in the absence of IL-21 signaling (IL-21R KO), effector CD8 T cell response to E.cuniculi infection was reduced both in terms of number and polyfunctionality. T follicular helper cells (TFH) are considered to be the major source of IL-21 and this CD4 T cell subset is critical for the formation of germinal centers, which is dependent on signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) expression. SAP knock out animals were used to study the role of this CD4 T cell subset in programing of effector CD8 T cell response against E.cuniculi. Intracellular staining analysis showed that TFH (ICOShiPD1hi CD4 T cells) are the main producers of IL-21 during early infection. As compared to wild type animals, SAP-/- mice exhibited lower IL-21 production at day 5-post infection. Interestingly, although the knock out mice exhibited increased short-lived effector CD8 T cell response (SLEC; KLRG1+CD127-) in terms of numbers, their polyfunctionality (IFNg production and significantly impaired cytotoxicity) was reduced. Moreover, activation status of SAP deficient SLECs (based on CD43 staining), in comparison to cells from wild type mice was also decreased. These findings strongly suggest that early IL-21 production by TFH may be critical for optimal effector CD8 T cell immunity against E.cuniculi infection

Effector CD8 T cell immunity in microsporidial infection: a lone defense mechanism.

Microsporidia are a group of pathogens, which can pose severe risks to the immunocompromised population such as HIV infected individuals. The expertise to diagnose these pathogens is limited and therefore their prevalence is believed to be much higher than what is currently known. In a mouse model of infections, it has been reported that CD8 T cells are the primary effector cells responsible for protecting the infected host. As the infection is acquired via per-oral route, CD8 T cells in the gut compartment apparently act as a first line of defense against the pathogens. Thus, generation of a robust CD8 T cell response that exhibits polyfunctional ability is critical for host survival. In this review, we describe the effector CD8 T cells generated during microsporidial infection and underline the factors that may be essential for the elicitation of protective immunity against this understudied but significant pathogen. Overall, this review will highlight the necessity for a better understanding of the development of the CD8 T cell response in gut associated lymphoid tissue (GALT) and provide some insights into therapies that may be used to restore defective CD8 T cell functionality in an immunocompromised situation