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During the course of an immune response, CD4+ T helper cells differentiate into a number of subsets including: T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. The functional diversity of CD4+ T effector cells results in a coordinated, pathogen-specific immune response. For example, the production of IFNγ by TH1 cells is vital for the clearance of intracellular pathogens, while TFH cell engagement with cognate B cells is required for germinal center (GC) formation and the generation of pathogen- and vaccine- induced antibody production. The development of CD4+ subsets is contingent on extracellular signals, in the form of cytokines, and downstream transcriptional networks responsible for promoting the unique gene expression profile for each subset while simultaneously suppressing alternative cell fates. However, the exact composition of, and stage-specific requirements for, these environmental cytokines and transcription factor networks in the governance of TFH cell differentiation remain incompletely understood. The work in this dissertation seeks to understand how cell-extrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Here, we demonstrate that in response to decreased IL-2 and constant IL-12 signaling, T helper 1 (TH1) cells upregulate a TFH-like phenotype, including expression of the TFH lineage defining transcription factor Bcl-6. Intriguingly, our work established that signals from IL-12 were required for both the differentiation and function of this TFH-like population. Mechanistically, IL-12 signals are propagated through both STAT3 and STAT4, leading to the upregulation of the TFH associated genes Bcl6, Il21, and Icos, correlating with increased B cell helper activity. Conversely, exposure of these TFH-like cells to IL-7 results in the STAT5-dependent repression of Bcl-6 and subsequent inhibition of the TFH phenotype. Finally, we describe a novel regulatory mechanism wherein STAT3 and the Ikaros zinc finger transcription factors Ikaros and Aiolos cooperate to regulate Bcl-6 expression in these TFH-like cells. Collectively, the work in this dissertation significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines. / Ph. D. / Specialized cells called T helper cells serve as a critical interface between the innate (first line of defense) and adaptive (specialized and long-term) immune systems. During the course of an infection, T helper cells are responsible for orchestrating the immune-mediated elimination of invading viruses, bacteria, and parasites. This wide breadth of functionality is achieved through the formation of distinct T helper subsets including T helper 1 (TH1), TH2, TH17, and T follicular helper (TFH) populations. Individual subsets have distinct developmental requirements and have unique functions within the immune system. For example, TFH cells are required for the production of effective antibodies that recognize invading pathogens, leading to their subsequent elimination. This naturally occurring process is the basis for a number of modern medical therapies including vaccination. Conversely, aberrant generation of antibodies that recognize host tissues can result in the onset of various autoimmune diseases including lupus, multiple sclerosis, and crohn’s disease. Due to the importance of TFH cells to human health, there is intense interest in understanding how these cells are formed. It is recognized that the generation of these therapeutically important immune cells is mediated by numerous cell-extrinsic andintrinsic influences, including proteins in their cellular environment called cytokines, and important proteins inside of the cell called transcription factors. However, as this is a complicated and multi-step process, many questions remain regarding the identity of these cytokines and transcription factors. The work in this dissertation seeks to understand how cellextrinsic cytokine signals and cell-intrinsic transcription factor activities are integrated to properly regulate TFH cell development. Collectively, this body of work significantly advances our understanding of the regulatory mechanisms that govern TFH cell differentiation, setting the basis for the rational design of novel immunotherapeutic strategies and increasingly effective vaccines.

The ability of cells within the adaptive immune system to develop into specialized subsets allow for a robust and tailored immune response in the advent of an infection or injury. Here, CD4+ T-cells are a crucial component within this system, with subsets such as TH1, TH2, TH17, TFH and TREG cells playing vital roles in propagating cell-mediated immunity. For example, TH1 cells are essential in combating intracellular pathogens such as viruses, while TFH cells communicate with B-cells to optimize antibody responses against an invading pathogen. The development (and functionality) of these subsets is ultimately dictated by the appropriate integration of extracellular cues such as cytokines with cell intrinsic transcription factors, thereby promoting the necessary gene profile. Moreover, the observation that T-helper cells could exhibit a flexible nature (i.e having shared gene profiles and effector functions) not only demonstrate the efficiency of our immune system but also how such flexibility could have unintended consequences during adverse events such as autoimmunity. An important mediator of such flexibility is cytokines. However, the complete network of factors that come together to co-ordinate cytokine mediated plasticity remain unknown. Thus, the work in this dissertation hope to delineate the factors that collaborate to regulate cytokine induced T-helper cell flexibility. As such, we see that in the presence of IL-2, the Ikaros Zinc Finger (IkZF) transcription factor Eos is upregulated in TH1 cells, with this factor playing a significant role in promoting regulatory and effector functions of TH1 cells. Moreover, we show that Eos forms a novel protein complex with STAT5 and promotes STAT5 activity in TH1 cells. However, depleting IL-2 from the micro-environment leads to the upregulation of two other members within the IkZF family, Ikaros and Aiolos. Aiolos in turn collaborate with STAT3, induces Bcl-6 expression within these cells, thus promoting these cells to exhibit characteristic features of TFH cells. The work in this dissertation hopes to advance our understanding of the regulatory mechanisms involved in cytokine mediated T-cell flexibility thereby hoping to open new avenues for the development of novel therapeutic strategies in the event of autoimmunity. / Ph. D. / T-helper (TH) cells are an important component of the immune system, as these cells aid in the fight against pathogens by secreting factors that either accentuate the inflammatory response during infection or attenuate immune responses post infection. Such effects are made possible because T-helper cells can differentiate into a variety of subsets, with each subset being an important mediator in maintaining immune homeostasis. For example, the T-helper cell subset called TH1 plays a vital role in the fight against intracellular pathogens such as viruses and certain parasites, while T-follicular helper (TFH) cells aid in the production of antibodies specific to the invading pathogen. The development of such subsets occur when cell extrinsic signals, called cytokines, lead to the activation or induction of cell intrinsic proteins called transcription factors. Interestingly, research over the years have shown that T-helper cells are highly adaptable in nature, with one subset having the ability to attain certain characteristic features of other subsets. This malleable nature of T-helper cells relies on several factors, with cytokines within the micro-environment being an important one. Although this form of flexibility is efficient and beneficial at times, it can also be detrimental, as such flexibility is known to promote certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Such detrimental effects are thought to be due to cytokines within the environment. Therefore understanding how cytokines influence the flexible nature of T-helper cells is important; as controlling such flexibility (either by regulating cytokines or the transcription factors activated as a consequence) could prevent the propagation of undesired T-helper cell functions. As such, the work in this dissertation hopes to uncover how one such cytokine, termed Interleukin-2 (IL-2) mediates the flexibility between TH1 and TFH cells. The work highlighted in this dissertation broadens our understanding of how cytokines influence T-helper cell development and flexibility, and consequently allows the design of novel therapeutic strategies to combat autoimmune diseases.

Pulmonary arterial hypertension (PAH) is a rare, devastating disease with no cure. Current treatment consists of a cocktail of vasodilators which relieve symptoms of PAH but do not treat the cause. Thus, there is a need for novel drugs that target the underlying pathological causes of PAH. PAH is a multi-factorial, but one key contributor is the pro-inflammatory cytokine IL-6 which stimulates pro-inflammatory and pro-angiogenic signalling mediated by the JAK/STAT pathway. One way in which IL-6 signalling via JAK/STAT is inhibited is via SOCS3 in a type of negative feedback loop whereby IL-6 induces transcription of SOCS3, which then attenuates further JAK/STAT signalling. SOCS3 can also be induced by cAMP. This is interesting as prostanoids, a type of drug used in the treatment of PAH due to its vasodilator effects and the only type to show any efficacy improving the life expectancy of PAH patients, acts by mobilising cAMP. Thus, prostanoid stimulation of cAMP could potentially limit IL-6 signalling via the induction of SOCS3. This is a novel mechanism of prostanoids which has not previously been considered. This study investigated the capability of prostanoids to limit the pro-inflammatory/pro-angiogenic effects of IL-6 that enable PAH to develop. Initial experiments confirmed that vascular endothelial cells responded to prostanoids which increased SOCS3 and limited IL-6 signalling activity. Further experiments utilising SOCS3 KO endothelial cell models demonstrated prostanoid inhibition of IL-6 signalling was due in part to SOCS3. In conclusion, this project has confirmed that prostanoids do limit the pro-inflammatory effects induced by IL-6 and that this is in part due to SOCS3. Although the exact mechanism is yet to be discovered, it will be beneficial in the treatment of PAH as it provides currently unexploited drug targets which can be considered for future PAH therapies. / British Heart Foundation

Une petite population de lymphocytes T exprimant les deux corécepteurs CD4 et CD8 et appelée double positive (DP), a été détectée dans le sang périphérique de donneurs sains et de patients atteints de diverses pathologies dont la sclérose en plaques (SEP). Nous avons émis l’hypothèse qu’il s’agissait de lymphocytes T hautement activés pouvant contribuer à l’inflammation chronique présente dans la SEP. Nous avons comparé les cellules T DP obtenues du sang de donneurs sains et de patients atteints de la SEP et non traités. La fréquence des cellules DP était similaire chez les patients et les donneurs sains. La proportion de lymphocytes T DP qui exprimaient les chaines du récepteur de l’interleukine-15 (IL-15) était plus élevée que pour les autres populations lymphocytaires. Des mesures d’induction de la phosphorylation du STAT5 (signal transducer and activator of transcription) ont démontré que les cellules DP ont répondu à des doses plus faibles et pour de plus longues périodes à l’IL-15 comparativement aux autres lymphocytes T. Le pourcentage de lymphocytes T DP ayant la capacité de produire l’interféron-gamma et des enzymes lytiques était élevé chez les témoins sains mais ces niveaux étaient significativement réduits chez les patients atteints de la SEP. La caractérisation phénotypique de cellules DP a suggéré que ces cellules ont des propriétés similaires aux lymphocytes T activés. Bien qu’il ne s’agisse que d’une caractérisation partielle, il semble que les lymphocytes T DP perdent une partie de leurs propriétés chez les patients atteints de la SEP. / A small population of T lymphocytes expressing both CD4 and CD8 called double positive (DP) T lymphocytes has been detected in the peripheral blood of healthy donors and patients affected by different pathologies such as multiple sclerosis (MS). We hypothesize that these cells represent a highly activated T lymphocyte subset that could contribute to the characteristic inflammation found in MS. Thus, we compared DP T cells from healthy donors to those from untreated MS patients. We found similar frequencies of DP T lymphocytes between both groups. A higher percentage of DP T lymphocytes expressed the IL-15R (interleukin 15 receptor) than other T cell populations. Moreover, IL-15 triggered the phosphorylation of STAT5 in a greater proportion of CD4+CD8+ T lymphocytes compared to other T cells. A greater percentage of CD4+CD8+ T lymphocytes can produce interferon gamma and lytic enzymes compared with other T cell subsets. However, those levels were drastically lower in MS patients. The phenotypic characterization of the DP cells suggests they have similar properties as activated T cells. Even though the characterization process is still in its infancy, it appears that the DP T cells may lose some of their properties in MS patients.

<p>In order to make development aid more efficient, a large number of donors, including Sweden, signed the so called Paris Declaration in 2005. The Declaration gives the partner countries more responsibility for their own development and aims to make he development aid provided by donor countries more measurable. It has been referred to as a paradigm shift within this policy area due to its far‐reaching goals.</p><p>The Declaration has consequences for all actors in the development aid community, and this thesis aims at outlining and analyzing the effects of the Declaration on the Swedish non‐governmental organisations which hold a frame agreement with the Swedish International Development Agency (SIDA). As an increasing part of evelopment aid is being channelled through NGOs and they hold an important role in the area, they are interesting subjects of study.</p><p>The analysis is conducted from a society‐centred governance perspective, which focuses on how different actors in society shape public policy. The perspective hallenges the view on the state as dominating unilaterally and takes into account the diversity of actors involved in policy‐making, such as NGOs.</p><p>The result of the study is, among other things, that the character of the relationships and interactions between Swedish NGOs and SIDA varies, and can be described as either a more traditional hierarchical model or co‐governing. Furthermore, the Paris Declaration is perceived by the NGOs as being a step in the right direction rather than a paradigm shift at all level.</p><p> </p> / <p>För att göra utvecklingsbistånd effektivare, undertecknade ett stort antal givare, däribland Sverige, den så kallade Parisdeklarationen 2005. Deklarationen ger samarbetsländerna ett större ansvar för sin egen utveckling och syftar till att göra biståndet från givarländerna mer mätbart. Man har kallat detta ett paradigmskifte inom området på grund av sina långtgående mål.</p><p>Deklarationen har konsekvenser för alla aktörer inom området utvecklingsbistånd, och denna uppsats syftar till att beskriva och analysera de effekter som deklarationen har på de svenska icke‐statliga organisationer som har ett ramavtal med SIDA. Eftersom en allt större del av utvecklingsbiståndet kanaliseras genom enskilda organisationer och de innehar en viktig roll i området, är de intressanta att studera.</p><p>Analysen görs utifrån ett samhällsorienterat governance perspektiv som fokuserar på hur olika aktörer i samhället utformar den offentliga politiken. Perspektivet utmaningar uppfattningen om att staten ensidigt dominerar och tar hänsyn till mångfalden av aktörer i det politiska beslutsfattandet, till exempel icke‐statliga organisationer.</p><p>Resultaten av undersökningen är bland annat att karaktären av de relationer och interaktioner mellan svenska icke‐statliga organisationer och SIDA varierar, och kan beskrivas som traditionellt hierarkisk, eller samarbetsbaserad (co‐governing). Vidare uppfattas Parisdeklarationen av icke‐statliga organisationer som ett steg i rätt riktning, snarare än ett paradigmskifte på alla nivåer.</p>

<p>Denna uppsats huvudsyfte var att studera debatten i den kyrkliga pressen i samband med separationen mellan kyrka och stat år 2000.  Undersökningen har visat att  genomförandet av separationen mellan kyrka och stat tillsammans med de organisatoriska och juridiska förändringar som detta innebar orsakade en stundtals kraftig debatt i kyrkopressen. I min undersökning har jag följt debatten kring fyra av de hetaste debattfrågorna och även belyst en av de konflikter som uppstod genom det utbredda missnöjet mot kyrkordningen. Studien har visat att det uppstod splittringar inom kyrkan mellan prästerskapet och kyrkans högre ledning, framförallt kyrkomötet, och att missnöjet mot separationsbeslutet och kyrkoordningen var utbrett bland denna grupp. Uppsatsen har även visat att kyrkan tiden efter undersökningens spektrum har drabbats av en del av de svårigheter och motgångar, främst genom minskat medlemsantal och försämrad ekonomi, som förutspåddes bland en del av debattörerna under debatten 1995-2000.</p>

<p>Genom att använda folktro och religion skapade den Japanska regimen under två eror, Meji och Showa, ett instrument för att tygla folket och ge obehindrad makt till toppskiktet i samhället. Man underströk kejsarfamiljens gudomliga arv som släkting till dem mäktigaste kamin i gudavärlden solgudinnan Amaterasu. Som släkting till henne var han att betrakta som gud och fick aldrig ifrågasättas. Det Japanska folket var inte heller vilket folk som helst utan ett härskarfolk som även det hade gudomlig härkomst. När folket sedan genom mängder av propaganda från skolväsendet upp igenom hela samhället indoktrinerats om sin och kejsarens överhöghet var det dags att visa resten av världen sin gudomlighet. Genom att besegra sina fiender i krig blev övertygelsen än större på hemmafronten och Kokka Shinto tycktes mer och mer sitta inne med sanningen. Japan var riktigt nära att slå ut den amerikanska flottan under andra världskriget, men en serie förluster satte stopp för framgångarna och Japan besegrades. Den amerikanska ockupationsmakten identifierade Kokka Shinto som skyldig till aggressionerna på samma sätt som nazismen var för Tyskland.</p><p>Kokka Shinto hjälpte till att göra Japan till en fascistisk stat precis som syftet var med den. Från början av Mejirestorationen till slutet av Andra Världskriget var Kokka Shinto en framgångssaga för ultranationalisterna men de allierades seger krossades Statsshinto. Det finns dock kvarlämningar av Statsshinto i Japan och när en Japansk premiärminister kan besöka Yasukuni-templet utan att tvingas avgå visar landet att man ännu har en bit att vandra innan man helt har kastat av sig sitt nationalistiska och fascistiska ok.</p><p>Slutsatsen blir därför att jag inte anser att Kokka Shinto är en religion utan snarare mäktiga mäns sluga utnyttjande av folktro och vidskeplighet i syfte att ta över ett land. Kokka Shinto är en veritabel våldtäkt på en legitim religion men genom att använda samma mytologi och historia köper man sig legitimitet. Man måste som utomstående vara mycket distinkt i att skilja på Shinto och Kokka Shinto ungefär på samma sätt som man skiljer på Socialism från Nationalsocialism. Fram till 1868 var Shinto en mycket tolerant religion och efter 1945 är det så återigen, det finns dock ett nationellt tema i Shinto som onda krafter kan utnyttja.</p>

<p>The aim of this paper is to describe and explain how the separation between state and church effects the power relations between state and religious groups and organizations. Former state church, The Swedish church, is in this paper, not included in the definition of religious groups. The reform (“stat-kyrka reformen”) took place between 1995 and year 2000.I’m examining if religious groups had any influence on the reform. My expectation is to give a clearer picture of religious groups and its power position in Swedish politics and society. A process-tracing method is used. I use different theories, theory of power and influence and theory of collective action. The reason for the decision to separate church and state was to handle social changes such as increasing secularism, pluralism and multiculturalism. This paper can however conclude that the state, after the reform, has shown an even greater, less secular, determination to connect with religious groups. I can also conclude that these religious groups had influence on the reform itself, partly because of its power resources and partly because its ability for collective actions.</p>

Denna uppsats huvudsyfte var att studera debatten i den kyrkliga pressen i samband med separationen mellan kyrka och stat år 2000.  Undersökningen har visat att  genomförandet av separationen mellan kyrka och stat tillsammans med de organisatoriska och juridiska förändringar som detta innebar orsakade en stundtals kraftig debatt i kyrkopressen. I min undersökning har jag följt debatten kring fyra av de hetaste debattfrågorna och även belyst en av de konflikter som uppstod genom det utbredda missnöjet mot kyrkordningen. Studien har visat att det uppstod splittringar inom kyrkan mellan prästerskapet och kyrkans högre ledning, framförallt kyrkomötet, och att missnöjet mot separationsbeslutet och kyrkoordningen var utbrett bland denna grupp. Uppsatsen har även visat att kyrkan tiden efter undersökningens spektrum har drabbats av en del av de svårigheter och motgångar, främst genom minskat medlemsantal och försämrad ekonomi, som förutspåddes bland en del av debattörerna under debatten 1995-2000.