Influence des oestrogènes sur la biologie des cellules dendritiques

Les données épidémiologiques montrent des différences entre les sexes dans l'immunité. Les femmes ont des réponses immunes plus fortes que les hommes et sont donc moins œsusceptibles aux infections mais, en contrepartie, développent plus fréquemment des maladies auto-immunes, telles que le lupus érythémateux disséminé (LED). De nombreuses données dans la littérature suggèrent que les œstrogènes contribueraient à ce dimorphisme sexuel. Nous avons analysé les effets du 17-oestradiol (E2) sur le développement et les fonctions effectrices des cellules dendritiques (DC). Dans un premier temps, nous avons montré dans un modèle in vitro que l'E2, par l'activation des récepteurs aux œstrogènes (ER), était essentiel à la différenciation et à l'acquisition des fonctions des DC. Nous avons démontré que les DC différenciées en absence d'E2 présentaient un phénotype immature associé un défaut d'activation des lymphocytes T CD4. Nous avons ensuite analysé l'effet de l'E2 sur une autre population de DC, les DC plasmacytoïdes (pDC) dont l'activation et la production d'IFN-I sont impliquées dans le développement de maladies auto-immunes telles que le LED. Il avait été rapporté que les pDC de femmes produisaient plus d'IFN-I en réponse à l'activation des TLR. Nous avons pu montrer que cette différence était attribuable aux œstrogènes. Nous avons démontré chez la souris que, l'ovariectomie conduisait à une diminution de la production de cytokines par les pDC après activation des TLR, alors que le traitement à l'E2 l'amplifiait. Cet effet était dépendant de la signalisation de l'ER dans le compartiment hématopoïétique. Nous avons pu confirmer ces résultats dans une étude clinique. Nos travaux montrent que les œstrogènes sont des modulateurs importants du développement et des fonctions effectrices de différentes populations de DC. Nous avons mis en évidence des effets pro-inflammatoires sur les fonctions des DC, qui pourraient expliquer les différences observées dans l'immunité et l'auto-immunité entre les sexes.Epidemiological data show sex differences in immunity. Women have stronger immune responses than men and are less susceptible to infection but, in turn, develop more frequent autoimmune diseases such as systemic lupus erythematosus (SLE). Data in the literature suggest that estrogen contributes to sexual dimorphism. We analyzed the effects of 17-estradiol (E2) on the development and effector functions of dendritic cells (DC). We first show in an in vitro model that E2, by activating estrogen receptor (ER) was essential for the differentiation and acquisition of DC functions. We demonstrate that DC differentiated in the absence of E2 had an immature phenotype associated with a deficiency in CD4+ T cell activation. We then analyzed the effect of E2 on a different population of DC, plasmacytoid DC (pDC), whose activation and production of IFN-I are involved in the development of autoimmune diseases such as SLE. It was reported that women pDC produced more IFN-I in response to TLR activation. Here, we have show that this difference is due to estrogen. We demonstrated, in mice, that ovariectomy led to a decrease in cytokine production by pDCs after TLR activation, whereas E2 treatment amplified it. This effect was dependent on ER signaling in the hematopoietic compartment. We were able to confirm these results in a clinical studying in which post-menopausal women treated with E2 showed a markedly enhanced TLR-7- and TLR-9-dependent production of IFN- by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In conclusion, our work shows that estrogens are important modulators of development and effector functions of several DC populations. We have highlighted the pro-inflammatory effect of E2 on the functions of DC, which may account for sex-based differences in autoimmune and infectious diseases

Physiological Regulation of Innate Lymphoid Cells

Discovery of innate lymphoid cells (ILCs) have provoked a paradigm shift in our understanding of the immune protection. Their constitutive presence and activity at the body's barrier surfaces ensure the maintenance of the tissue homeostasis and immune protection. This complex family has distinct and non-redundant functions that can have both beneficial and detrimental effects on disease outcome. The capacity of ILCs to perform their function effectively relies on their ability to sense and integrate intrinsic and extrinsic signals. Recent studies have shown that ILCs are not only sensitive to pathogen-derived stimuli but are also very well equipped to sense host-derived signals such as neuropeptides, hormones, and metabolites. The integration of these signals represents a complex and constant cross-talk between the immune system and the physiological systems of the body, including the nervous, endocrine, digestive, and reproductive systems. The physiological regulation of ILCs constitutes an important step in our understanding of the events leading to the protective and pathological properties of these cells. This review summarizes the recent advances in the understanding of the regulation of ILCs by physiological signals and their consequences on the maintenance of tissue homeostasis

Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells

The cytokine IL-15 is required for natural killer (NK) cell homeostasis; however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo

Mediators of lifestyle behaviour changes in obese pregnant women. Secondary analyses from the DALI lifestyle randomised controlled trial

A better understanding of what drives behaviour change in obese pregnant overweight women is needed to improve the effectiveness of lifestyle interventions in this group at risk for gestational diabetes (GDM). Therefore, we assessed which factors mediated behaviour change in the Vitamin D and Lifestyle Intervention for GDM Prevention (DALI) Lifestyle Study. A total of 436 women, with pre-pregnancy body mass index ≥29 kg/m 2 , ≤19 + 6 weeks of gestation and without GDM, were randomised for counselling based on motivational interviewing (MI) on healthy eating and physical activity, healthy eating alone, physical activity alone, or to a usual care group. Lifestyle was measured at baseline, and at 24–28 and 35–37 weeks of gestation. Outcome expectancy, risk perception, task self-efficacy and social support were measured at those same time points and considered as possible mediators of intervention effects on lifestyle. All three interventions resulted in increased positive outcome expectancy for GDM reduction, perceived risk to the baby and increased task self-efficacy. The latter mediated intervention effects on physical activity and reduced sugared drink consumption. In conclusion, our MI intervention was successful in increasing task self-efficacy, which was related to improved health behaviours

Shaping Innate Lymphoid Cell Diversity

Innate lymphoid cells (ILCs) are a key cell type that are enriched at mucosal surfaces and within tissues. Our understanding of these cells is growing rapidly. Paradoxically, these cells play a role in maintaining tissue integrity but they also function as key drivers of allergy and inflammation. We present here the most recent understanding of how genomics has provided significant insight into how ILCs are generated and the enormous heterogeneity present within the canonical subsets. This has allowed the generation of a detailed blueprint for ILCs to become highly sensitive and adaptive sensors of environmental changes and therefore exquisitely equipped to protect immune surfaces

Differentiation and diversity of subsets in group 1 innate lymphoid cells

NK cells were first identified in 1975 and represent the prototypical group 1 innate lymphoid cell (ILC). More recently, the discovery of new members of the ILC family has highlighted the complexity of this innate lymphoid lineage. Importantly, it has been recognized that different subsets exist within the group 1 ILC, which have potential roles in mediating immune protection and immunosurveillance, and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the different group 1 ILC, which have been identified to date and discuss how heterogeneity within this expanding family may have arisen

Terminal differentiation of dendritic cells

Dendritic cells (DCs) are essential for the initiation of an effective immune response. Despite this, our understanding of the molecular regulation of this important cell type has lagged significantly behind that of other lymphoid populations such as B and T cells, but recent development of various tools has greatly facilitated progress in the field. Here, we review the transcription factors that drive peripheral DC subset fate decisions. While Pu.1, Ikaros, and Gfi-1 are essential for precursor DCs to give rise to monocytes, conventional DCs, and plasmacytoid DCs, the balance between E2-2 and Id2 directs committed precursors along a pDC or cDC lineage, respectively. Several transcription factors such as Batf3, Nfil3, and Id2 are required for different DC subsets at steady-state and drive segregation into the individual DCs subsets late in development in the CD8 lineage. During inflammation, CD8-expressing DCs emerge that feature many of the hallmarks of classical CD8α DCs but surprisingly do not depend on the same transcription factors. Thus, the immune system has developed two pathways of DC differentiation that enable it to maintain homeostatic balance and to respond rapidly to the emergency requirement for DCs that might occur during infection

Natural killers or ILC1s? That is the question

International audienc

Shaping Innate Lymphoid Cell Diversity

Innate lymphoid cells (ILCs) are a key cell type that are enriched at mucosal surfaces and within tissues. Our understanding of these cells is growing rapidly. Paradoxically, these cells play a role in maintaining tissue integrity but they also function as key drivers of allergy and inflammation. We present here the most recent understanding of how genomics has provided significant insight into how ILCs are generated and the enormous heterogeneity present within the canonical subsets. This has allowed the generation of a detailed blueprint for ILCs to become highly sensitive and adaptive sensors of environmental changes and therefore exquisitely equipped to protect immune surfaces

Innate Lymphoid Cell Biology: Lessons Learnt from Natural Killer Cells

Group 1 innate lymphoid cells (ILC) comprise the natural killer (NK) cells and ILC1 which reside within peripheral tissues. Several different ILC1 subsets have recently been characterised, however no unique markers to define these subsets have been identified. Whether ILC1 and NK cells are in fact distinct lineages, or alternately exhibit transitional molecular programs, that allow them to adapt to different tissue niches remains an open question. NK cells are the prototypic member of the Group 1 ILC and have been historically assigned the functions of what now appears to be a multi-subset family that are distributed throughout the body. This raises the question of whether each of these populations mediate distinct functions during infection and tumour immunosurveillance. Here, we review the diversity in the Group 1 ILC subsets with regards to their transcriptional regulation, localization, mobility and receptor expression and highlight the challenges in unraveling the individual functions of these different populations of cells