La GVH chronique (cGVHD) est une complication fréquente de l’allogreffe de cellules souches hématopoïétiques (CSH) dont la physiopathologie demeure partiellement comprise. Les données disponibles ont établi le rôle des lymphocytes T (LT) et B (LB) au cours de la cGVHD, mais la qualité de leur interaction et les sous-types de LT impliqués restent à définir. L’interaction entre les LT et les LB se fait au niveau du centre germinatif (CG) aboutissant à la production de LB mémoires et de cellules productrices d’anticorps de haute affinité grâce aux signaux d’aide reçus par les LT folliculaires helpers (TFH) finement contrôlés par une population régulatrice (TFR). La possibilité d’interroger les évènements se déroulant au niveau du CG par l’analyse de leur contingent circulant (c) nous a permis de mieux comprendre la physiopathologie de la cGVHD. En effet, la signature phénotype des cTFH suggère un gain de fonction au cours de la cGVHD, confirmée par étude fonctionnelle, et corrélant avec le phénotype des LB observé. De plus, les mécanismes de régulation apparaissent défectueux au cours de la cGVHD, puisque les cTFR présentent un défaut numérique expliqué par un défaut de résistance à l’apoptose et de prolifération. D’autre part, nous avons analysé une population de LT CD4+CD146+CCR5+, leur conférant une capacité de migration au travers des structures endothéliales et vers les sites inflammatoires. Cette population est significativement augmentée au cours de la cGVHD, et les modèles murins de cGVHD recevant des splénocytes de souris CD146-/- voient leur score clinique amélioré. L’expression de CD146 est associée à une polarisation Th17 justifiant un traitement par TMP778 (inhibiteur de RORγt) améliorant la cGVHD chez la souris. L’analyse de ces populations révèle des anomalies de la balance effecteurrégulateur et de potentielles cibles thérapeutiques à évaluer en clinique. / Chronic GVHD (cGVHD) remains a major complication of allogeneic stem cell transplantation and its pathogenesis poorly understood. Previous reports established the role of T cells and B cells during cGVHD, but the quality of their interaction and T cell subsets involved remain to be defined. T cell – B cell crosstalk occurs in the germinal center generating memory B cells and high affinity antibody secreting cells consecutively to signals provided by T follicular helper cells (TFH) which are tightly controlled by a regulatory subset (TFR). The opportunity to interrogate events occurring in the germinal center through the analysis of their circulating contingent (c), allowed us to better understand cGVHD pathogenesis. cTFH phenotypic signature suggest an enhanced function during cGVHD, confirmed in functional studies, and correlating with observed B cell phenotype. In addition, regulatory mechanisms appeared defective during cGVHD, as cTFR showed a numerical deficiency, explained by a defect in resistance to apoptosis and low proliferative capacity. We also studied a T cell subset expressing CD4+CD146+CCR5+, giving the capacity to migrate through endothelial structures and toward inflammatory sites. This population is significantly increased during cGVHD, and cGVHD murine models receiving splenocytes from CD146-/- mice showed improved clinical score. CD146 expression is associated with a Th17 polarization justifying a treatment by TMP778 (RORγt inhibitor) improving cGVHD in mice. The analysis of these different populations revealed an abnormal effector-regulator balance and potential therapeutic targets to evaluate in clinic.

In this study we have investigated fertility levels during periods of unusually high unemployment levels. Our research questions were: 1. To what extent does fertility levels change during periods of higher unemployment? 2. Can family policies affect changes of fertility levels during these periods? Our hypothesis states that firstly, fertility levels are expected to be lower during periods of higher unemployment, due to households perceiving a lower level of economic security. Secondly, effective family policies should counter this effect, making unemployment having less of an effect on household fertility decisions, due to family policy lowering the economic risks associated with having a child. We performed an analysis in two parts. In the first part we divided countries into groups based on which countries had experienced a period of higher unemployment, and which countries had more or less generous family policies. The second part of our analysis was a regression analysis of TFR, unemployment and family policy variables. The results were in line with our first hypothesis: In our first analysis, the group of countries that were experiencing a period of higher unemployment also had a more negative development of fertility. In our regression analysis, we could observe a negative relationship between unemployment and fertility. On the other hand, our results could not support our second hypothesis: No individual family policy could be found to change the effect of unemployment on fertility levels.

Indiana University-Purdue University Indianapolis (IUPUI) / Follicular T helper (TFH) and regulatory (TFR) cells are two key classes of CD4+ T cells found in germinal centers (GCs). The primary role of TFH cells is to help B cells form GCs to produce high-affinity antibodies during an infection while the role of TFR cells remains controversial. The transcriptional repressor Bcl6 is essential for the differentiation of TFH, TFR and GCB cells and understanding signaling pathways that induce Bcl6 and TFH cell differentiation are important. We observed that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation by a pathway involving the metabolic sensor AMP kinase. The transcription factor Blimp1 represses both TFH cell differentiation and Bcl6 expression, and we show the major role of Blimp1 on TFH cell differentiation is to repress Bcl6 expression and not other genes in the TFH differentiation pathway. We also found Bcl6 positively regulates expression of the key TFH cell receptor PD-1 by inhibiting the repression of PD-1 by the transcription factor Tbet. The roles of TFH and TFR cells in controlling allergen-specific IgE were investigated using a peanut allergy model and strains of mice with alterations in the TFH and TFR pathways. We found TFR cells unexpectedly play an essential role in promoting and maintaining IgE production and anaphylaxis, as well as the GC reaction. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE and anaphylactic responses were significantly weakened. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GCB cell survival and IgE production. Blocking IL-10 signals mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Overall, these studies have defined novel roles of Bcl6, TFH and TFR cells in regulating antibody production by the GC reaction, and provide greater understanding of how allergic immune responses are controlled. / 2019-11-21

La réponse immunitaire humorale désigne l’ensemble des processus menant à la production d’anticorps suite à une stimulation du système immunitaire. Les lymphocytes T folliculaires régulateurs (Tfr) forment une population essentielle dans le contrôle de l’immunité humorale. Dotés de fonctions régulatrices comme les lymphocytes T régulateurs conventionnels (Treg), les Tfr joueraient un rôle majeur dans les mécanismes de régulation de la production d’anticorps suite à une stimulation. Ils pourraient, par exemple, contrôler l’aide apportée par les lymphocytes T folliculaires helpers (Tfh) aux cellules B leur permettant de se différencier en plasmocytes producteurs d’anticorps dans une structure hautement spécialisée appelée centre germinatif (CG). Suite au constat de la non-réponse des Tfr à l’interleukine (IL)-2, nous avons observé l’absence d’expression de la sous-unité du récepteur à l’IL-2 (CD25) sur ces cellules et ainsi donné de nouvelles bases à la caractérisation phénotypique des Tfr. Cette redéfinition restrictive de la population cellulaire a permis une description plus approfondie de ces cellules et la découverte d’un axe de régulation du CG dépendant de l’IL-1ß. La dualité de régulations observée entre d’une part l’axe Treg - lymphocytes T effecteurs contrôlé par l’IL-2 en dehors du CG et d’autre part l’axe Tfr - Tfh contrôlé par l’IL-1ß dans le CG nous a amenés à nous poser la question de l’origine et de la spécificité des Tfr en partie élucidée par une analyse du répertoire de ces populations. Nous avons mis en évidence une similarité en matière de distribution et caractéristiques globales des répertoires des cellules folliculaires qu’elles soient régulatrices (Tfr) ou non (Tfh). Il est également apparu une proximité de spécificités entre le répertoire des Treg et des Tfr confortant l’hypothèse d’une origine commune de ces deux populations. Ce travail de thèse a permis la découverte d’éléments importants de la biologie des Tfr, population impliquée dans le contrôle des régulations humorales. Il ouvre des perspectives relatives au contrôle de la production d’anticorps tant sa limitation - dans le contexte de maladies auto-immunes - que son exploitation dans le développement de stratégies vaccinales. / The immune humoral response offers the organism an efficient protection through the production of antibodies following an immune stimulation. Follicular regulatory T cell (Tfr) is an essential subset in the control of humoral immunity. These cells share with conventional regulatory T (Treg) cells regulatory functions and should play a major role in the control of antibody production following stimulation. As T follicular helper (Tfh) cells help is essential in the differentiation of B cell into antibody-producing plasma cells, one of the possible mechanisms of Tfr’s control could be the limitation of the Tfh cells’ help to the B cells. As a consequence of the non-response of Tfr cells to interleukin (IL)-2, we thoroughly revealed the CD25- phenotype of Tfr cells thus redefining the subset. This stringently-selected population allowed a fine-tuned characterization of Tfr cells and the discovery of an IL-1β axis regulating the germinal center responses. The dual regulation of T cells in secondary lymphoid organs, one between Treg and Teff cells regulated by IL-2 outside germinal centers and the other between Tfh and Tfr cells regulated by IL-1 inside GCs brought us to question the origin and specificity of Tfr cells. We partially answered this with a high-resolution analysis of these populations’ repertoires. We highlighted a similarity in the distributions and global characteristics of the follicular cells’ repertoires regardless their regulatory (Tfr) or not (Tfh) phenotype. We also brought out the major sharing between Treg and Tfr repertoires underpinning the hypothesis of a common origin for these populations. This work has disclosed important aspects of Tfr cells’ biology, a fundamental subset in the control of humoral immune responses. It opens many perspectives including the control of antibody production, negatively in the context of autoimmune diseases or its positive exploitation to enhance vaccine efficacy

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Introduction: Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials. Methods: Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Results: Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI. Discussion: Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

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Die Dissertation fragt nach den Ursachen der spezifisch niedrigen Geburtenrate in Ost- und Westdeutschland, die seit Mitte der siebziger Jahre deutlich unter dem Reproduktionsniveau liegt. Theoretisch wird die Frage behandelt, inwiefern die gewandelte gesellschaftliche Stellung der Frau – insbesondere ihre höhere Bildungs- und Erwerbspartizipation – mit der Verbreitung geringer Kinderzahlen in Verbindung steht. Für die Analysen werden Scientific Use Files der Mikrozensen 1973 bis 2008 verwendet; diese repräsentieren jährlich 0,7 Prozent der deutschen Bevölkerung. So kann gezeigt werden, dass innerhalb vergleichbarer soziostruktureller Gruppen kaum ein Rückgang der Kinderzahlen auftrat. Differenziert nach Berufsbildungsabschluss, Erwerbstätigkeit und Finanzierung des Lebensunterhaltes zeigt sich, dass einzig Frauen ohne Berufsbildung sowie Frauen, die das Hausfraumodell leben, durchschnittlich 2,0 Kinder haben – dies ist sowohl im Jahr 1982 wie auch 2008 in Westdeutschland der Fall. Innerhalb der Gruppe der erwerbstätigen Frauen liegen die Kinderzahlen je Frau deutlich niedriger. Die Gruppe der Hausfrauen, die ihren überwiegenden Lebensunterhalt durch ihren Ehemann finanziert, hat sich in Westdeutschland im Zeitvergleich seit dem Jahr 1982 von 50 auf 25 Prozent der Frauen halbiert. Dieser strukturelle Wandel hin zu einer unabhängigen weiblichen Lebensführung führte in Westdeutschland zu Kinderzahlen weit unter dem Reproduktionsniveau. Die empirische Analyse zeigt, dass strukturtheoretische Modelle mit klassischen Variablen wie Familienstand, Erwerbsumfang und Einkommen die Varianz der Kinderzahl heute besser erklären können als noch in den achtziger Jahren. Im Fazit scheint ein gesellschaftliches „cultural lag“ auf – die gesellschaftliche Unterstützung zur Vereinbarkeit von Beruf und Familie ist offensichtlich zu gering, so dass die Emanzipation der Frau in Deutschland den negativen Effekt niedriger Geburtenraten hervorbringt. / The study focuses on the causes of low birth rates in eastern and western Germany, which has been below the level of reproduction since 1975. Theoretically the changing position of women in society is considered and the possible connections between higher female education, the spread of female employment and low fertility rates are discussed. The analysis is based upon scientific use files of the German micro census from 1973 up to 2008; the data represent annually 0.7 percent of the German population. It is shown, that there is no decline in fertility within similar socio structural subgroups. Controlled by educational/vocational training, employment and female income (financial independence) it is shown that only women with no vocational training and women with no own income have 2.0 children per women – this result is significant for Western Germany in 1982 as well as in 2008. Within the group of employed women the mean number of children is much lower. But the group of housewives declined in half from 50 to 25 percent between 1982 and 2008. This structural change toward female independent lifestyle leads to a very low birth rate in Germany. The empirical analysis shows that classical models using structural variables like family status, employment and income are able to explain a considerable higher variance of birth rates today. Summing up there appears to be a “cultural lag”: women get emancipated, but the public support and the compatibility of work and family stays low, as well as the birth rates of employed women led to low overall birth rates.

L’objectif de la présente étude est de documenter la fécondité des Indiennes inscrites au Canada en fonction du traité historique d’affiliation. Les traités historiques sont des ententes légales qui lient le gouvernement du Canada et certains membres des Premières Nations et qui décrivent, notamment, les dispositions prévues à leur égard pour compenser la cession de leurs terres. Mêmes si les traités ont principalement une fonction légale, ils regroupent aussi des individus qui partagent des caractéristiques communes sur le plan culturel, linguistique, socioéconomique, territorial et historique. À partir de données extraites du Registre des Indiens, nous avons produit l’indice synthétique de fécondité (ISF) pour chacune des populations affiliées aux traités historiques pour les périodes 1994-1998, 1999-2003 et 2004-2008. Nous voulions savoir si la fécondité des Indiennes inscrites différait en fonction du traité d’affiliation, si on observait des changements dans le temps et si de grandes tendances pouvaient être identifiées selon les régions couvertes par les traités. Des différences importantes sont relevées, particulièrement entre les traités numérotés qui couvrent les Prairies et les traités de l’est du pays. Étant donné l’absence dans le Registre des Indiens, d’informations sur les caractéristiques sociales, culturelles et économiques des populations affiliées aux différents traités, il n’est pas possible d’avancer des explications précises concernant ces écarts. Toutefois, il est possible de proposer une association entre la fécondité du moment et certaines caractéristiques des populations affiliées aux traités historiques et les dimensions géographique et historique des traités. / This research aims to document the fertility of registered Indians in Canada in relation to their affiliation with historic treaties. The historic treaties are legal agreements, between the government of Canada and certain members of the First Nations, which describe lands surrendered and related compensation. Although the treaties have mainly a legal role, they apply to Indigenous peoples sharing similar characteristics along cultural, linguistic, socioeconomic, territorial and historical lines. We used anonymized data extracted from the Indian Register to produce the total fertility rate (TFR) for the population concerned by each historic treaty for the periods 1994-1998, 1999-2003 and 2004-2008. We wanted to know if the fertility of registered Indians differed by treaty memberships, if we observed changes over time and if notable trends could be identified depending on the regions covered by the treaties. Our analyses show that important differences exist, particularly between the numbered treaties, which cover the Prairies provinces, and the treaties populations of Eastern Canada. Since the data collected by the Indian Register do not contain information on social, cultural and economic characteristics of Indigenous peoples that could explain these differences, it is not possible to develop precise explanations of these variations. However, it is possible to propose an association between the fertility rate and the geographical and historic aspects of the treaties populations.