Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux.

Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan

The Coevolution of Economic and Political Development

This paper establishes a simple model of long run economic and political development, which is driven by the inherent technical features of di¤erent production factors, and political con‡icts among factor owners on how to divide the outputs. The main capital form in economy evolves from land to physical capital and then to human capital, which enables their respective owners (landlords, capitalists, and workers) to gain political powers in the same sequence, shaping the political development path from monarchy to elite ruling and …nally to full su¤rage. When it is too costly for any group of factor owners to repress others, political compromise is reached and economic progress is not blocked; otherwise, the political con‡icts may lead to economic stagnation

Le vieillissement du système immunitaire : du fondamental à la clinique

International audienceMajor progress in preventing, delaying or curing various pathologies normally encountered in old age results in a continuous improvement in life expectancy. However, understanding the underlying cause of the disparate comorbidities occurrence with aging remains a priority in order to propose adapted care for the older population. In one hand, aging profoundly impairs the immune system; it is characterized by many changes in haematopoiesis, adaptive and innate systems, and is associated with pro-inflammatory environment. In another hand, stressful events (acute or chronic) can also impact the immune system through the secretion of hormones, which are also altered with aging. Blooming evidences from psychoneuroimmunology field suggest that, in acute medical conditions, elderly people are not equal in their responses to stressors depending on many extrinsic and intrinsic parameters. These factors could interfere with elderly's ability to mount an effective immune response. The objective of this review is to provide an overview of the literature (from fundamental to clinical observations) to draw a global picture of immunosenescence. Understanding this process could enable us to target fundamental age-related pathways and thus open new avenues in improving both lifespan and health span.L’espérance de vie ne cesse d’augmenter en raison de progrès importants dans la prévention, le retard ou la guérison de diverses pathologies normalement rencontrées lors du vieillissement. Cependant, les progrès scientifiques et médicaux sont encore nécessaires pour comprendre la cause sous-jacente de l’occurrence disparate des comorbidités avec le vieillissement. D’une part, le vieillissement altère profondément le système immunitaire ; il est caractérisé par de nombreux changements de l’hématopoïèse, des systèmes adaptatifs et innés, associés à un environnement pro-inflammatoire. D’autre part, les événements stressants (aigus ou chroniques) peuvent également avoir un impact sur le système immunitaire par la sécrétion d’hormones, qui sont également altérées par le vieillissement. Le domaine de la psychoneuro-immunologie fournit maintenant des preuves que, dans les conditions médicales aiguës, les personnes âgées ne sont pas égales dans leurs réponses aux facteurs de stress. Des paramètres (extrinsèques et intrinsèques) pourraient interférer avec la capacité des personnes âgées à monter une réponse immunitaire efficace. L’objectif de cette revue est de fournir un aperçu de la littérature (des observations fondamentales aux observations cliniques) pour établir un panorama global de l’immunosénescence. Comprendre ce phénomène pourrait nous permettre de cibler des voies fondamentales liées à l’âge et ainsi ouvrir de nouvelles perspectives pour améliorer la durée de vie mais aussi pour se maintenir en bonne santé plus longtemps

A3.20 The calcium sensor stromal interaction molecule 1 (STIM1) controls regulatory B cell functions and its activity is impaired in Systemic Lupus Erythematosus patients.

International audienceBACKGROUND AND OBJECTIVES: The immunosuppressive function of regulatory B cells (Breg) is defective in B cells from systemic lupus erythematosus (SLE) patients. Since the Ca(2+) pathway is also altered in SLE B cells, the aim of the study was to explore the contribution of the Ca(2+) channel Orai1 and its regulator, the stromal interaction molecule 1 (STIM1), on regulatory B cell functions. MATERIALS AND METHODS: Thirty SLE patients and healthy controls (HC) were included in the study. Orai1 and STIM1 expressions were explored in CD40/CpG activated B cells, and in the stimulated (anti-CD3, anti-CD28 plus CpG-ODN 2006) T- and B- cell autologous co-culture Breg model. Transfection were used using either siRNAs to down-modulate STIM1 in SLE B cells, or either the cDNA STIM1 vector in HC B cells. RESULTS: After 3 days, in CD40/CpG activated HC B cells, and in HC B cells stimulated during co-cultures, acquisition of the Breg phenotype (IgD/CD38/CD24/CD5(high)) was associated with an over-expression of the Ca(2+) regulator STIM1 (x10.8 and x7.1 fold increase respectively). At day 4 and even more at day 5, STIM1 expression declined in co-cultures and this down-regulation was accompanied with IL-10 and TGF-beta up-regulation in B cells, FoxP3(+) regulatory T cell expansion, and a reduction of T cell proliferation. Expression of the Ca(2+) channel Orai1 was stable. In SLE B cells, STIM1 expression was overexpressed at basal level when compared to HC B cells (x4.3 fold) and remains elevated in B cells during all the time of the autologous co-culture (x8.8 fold). Then we hypothesised that maintaining high levels of STIM1 was critic in the regulatory capacity of SLE B cells. Accordingly, we demonstrated that STIM1 downregulation in SLE B cells, using a specific siRNA, was effective to restore IL-10, but not TGF-beta, expression, FoxP3(+) regulatory SLE T cell expansion, and SLE T cell inhibition. In HC B cells, forcing STIM1 expression, with a STIM1 vector, was effective to reproduce the abnormalities observed in SLE B cells. No association was observed between STIM1 expression at basal level and organ involvement, disease activity (SLEDAI), or serological parameters thus suggesting that STIM1 over-expression and Ca(2+) dysregulations are primary events in SLE. CONCLUSIONS: Altogether, this study reveals that acquisition of the Breg phenotype and Breg functions are tightly regulated by STIM1. Furthermore, this observation could provide innovative B-cell based treatment to convert B cells into immunosuppressive cells with applications in human autoimmunity and in SLE. KEY WORDS: lupus, regulatory B cells, calcium, STIM1, IL-10