Anne L Astier

University of Edinburgh, MRC Centre for Inflammation Research, Faculty Member

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Explorer Monocyte : T cell interaction regulates human T cell activation through a CD 28 / CD 46 crosstalk

T cell activation requires engagement of the T cell receptor and of at least one costimulatory mo... more T cell activation requires engagement of the T cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T cell activation has been reported several decades ago and the molecular mechanisms involved well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T cell differentiation from producing some IFN to secreting some potent anti-inflammatory IL-10, acquiring a so-called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T cell activation and IL-10 production. The observation that CD46 cleavage was reduced when PBMC were costimulated compared to purified naive T cells led us to hypothesize that interactions between different cell types within the PBMC were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4 + T cells are co-cultured with autologous monocytes. Indeed, monocyte:T cell co-cultures impaired CD46mediated T cell differentiation and coactivation, by reducing downregulation of surface CD46, lowering induction of the early activation marker CD69, as well as reducing the levels of IL-10 secretion. Blocking of CD86 could partly restore CD69 expression and cytokine secretion, demonstrating that the CD28-CD86 pathway regulates CD46 activation. Direct concomitant ligation of CD28 and CD46 on CD4 + T cells also modulated CD46 expression and regulated cytokine production. These data identify a crosstalk between two main costimulatory pathways and provide novel insights into the regulation of human T cell activation.

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Full spectrum of vitamin D immunomodulation in multiple sclerosis: mechanisms and therapeutic implications

Brain communications, Jun 30, 2022

Vitamin D deficiency has been associated with the risk of multiple sclerosis, disease activity an... more Vitamin D deficiency has been associated with the risk of multiple sclerosis, disease activity and progression. Results from in vitro experiments, animal models and analysis of human samples from randomized controlled trials provide comprehensive data illustrating the pleiotropic actions of Vitamin D on the immune system. They globally result in immunomodulation by decreasing differentiation of effector T and B cells while promoting regulatory subsets. Vitamin D also modulates innate immune cells such as macrophages, monocytes and dendritic cells, and acts at the level of the blood-brain barrier reducing immune cell trafficking. Vitamin D exerts additional activity within the central nervous system reducing microglial and astrocytic activation. The immunomodulatory role of Vitamin D detected in animal models of multiple sclerosis has suggested its potential therapeutic use for treating multiple sclerosis. In this review, we focus on recent published data describing the biological effects of Vitamin D in animal models of multiple sclerosis on immune cells, blood-brain barrier function, activation of glial cells and its potential neuroprotective effects. Based on the current knowledge, we also discuss optimization of therapeutic interventions with Vitamin D in patients with multiple sclerosis, as well as new technologies allowing in-depth analysis of immune cell regulations by vitamin D.

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Editorial: Dysregulation of Th17 and Treg cells in autoimmune diseases

Frontiers in Immunology, Feb 14, 2023

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Pharmacokinetics and absolute rectal bioavailability of hydrocortisone acetate in distal colitis

Alimentary Pharmacology & Therapeutics, Mar 31, 2007

The hydrocortisone pharmacokinetic profiles of hydrocortisone acetate foam (Proctocort) administe... more The hydrocortisone pharmacokinetic profiles of hydrocortisone acetate foam (Proctocort) administered rectally was assessed in healthy volunteers and patients with ulcerative colitis or X-irradiation colitis. Endogenous production of hydrocortisone was suppressed by dexamethasone. Comparison of these data with those obtained after intravenous administration enabled assessment of absolute bioavailability, which was 30.0 patients (P = 0.09). Maximal concentrations of hydrocortisone were also decreased in patients, 277 t-215 nmol/L us. 610 5 334 nmol/L (P = 0.03). There was a nonsignificant tendency to faster absorption of hydrocortisone in patients vs. healthy volunteers, as the times to peak concentration were, respectively, 2.5 & 1.2 h vs. 2.8 5 0.8 h (P = 0.64), and the mean absorption times were 1.96 f 1.45 h vs. 2.54 f 1.62 h (P = 0.46). Thus, rectal inflammation resulted in a lower absorption of 15.1 % in healthy volunteers vs. 16.4 f 14.8 % in

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Vitamin D promotes Tr1 differentiation through the CD46 pathway (178.18)

Journal of Immunology, May 1, 2012

The complement regulator CD46 induces a regulatory Tr1 phenotype, characterized by large amounts ... more The complement regulator CD46 induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 activation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D has an immunomodulatory role and may be beneficial in several pathologies, including MS. Herein, we show that, upon CD46 costimulation, Vitamin D strongly increased the IL-10:IFNγ ratio, characteristic of the CD46-induced Tr1 phenotype. This was correlated with the modulation of several markers known to control T cell activation. Vitamin D strongly promoted the expression level of CD28, CD25 and CTLA-4 on CD46-activated T cells, while it concomitantly decreased CD46 expression. Importantly, addition of Vitamin D could restore the defective IL-10 production observed in T cells from patients with MS. Hence, Vitamin D promotes anti-inflammatory responses by mainly acting on CD46, and might be beneficial for T cell responses in MS.

Levels Cells Reveals FLT3 as a Modulator of IL-10 RNA Interference Screen in Primary Human T

Etude du mode de production des rfcgamma solubles humains de basse affinite de type ii (rfcgammaiia). Caracterisation biochimique et fonctionnelle

Le mecanisme de production des rfcgammaiia solubles humains liberes par les cellules de langerhan... more Le mecanisme de production des rfcgammaiia solubles humains liberes par les cellules de langerhans, les plaquettes et les lignees megacaryocytaires a ete etudie. Une partie de ces recepteurs solubles sont directement secretes du fait de l'absence de la region transmembranaire due a un mecanisme d'epissage alternatif de l'exon codant pour cette region. Ils ont ete appeles rfcgammaiia2, par opposition a la forme membranaire designee sous le nom de rfcgammaiia1. Alors que les cellules de langerhans secretent des molecules solubles comprenant l'integralite des regions extra- et intra- cellulaires du rfcgammaiia2, les plaquettes et les cellules de la lignee megacaryocytaire dami liberent en majorite des molecules solubles ne possedant plus une partie de l'extremite c- terminale de la region intracytoplasmique, a la suite d'un clivage proteolytique. De telles molecules sont aussi retrouvees dans le serum humain. Le clonage de l'adnc codant pour le rfcgammaiia2 dans des vecteurs d'expression eucaryote ou procaryote nous a permis de montrer que ces molecules sont capables d'entrer en competition avec le recepteur membranaire equivalent pour la fixation d'immunscomplexes. Ils pourraient aussi agir directement sur des lignees cellulaires humaines n'exprimant pas d'igg a leur surface, ce qui suggere l'existence de recepteur(s) autre(s) que les igg membranaires

T Cell Regulation by the Environment

Frontiers research topics, 2015

Naïve T cells get activated upon encounter with their cognate antigen and differentiate into a sp... more Naïve T cells get activated upon encounter with their cognate antigen and differentiate into a specific subset of effector cells. These T cells are themselves plastic and are able to re-differentiate into another subset, changing both phenotype and function. Differentiation into a specific subset depends on the nature of the antigen and of the environmental milieu. Notably, certain nutrients, such as vitamins A and D, sodium chloride, have been shown to modulate T cell responses and influence T cell differentiation. Parasite infection can also skew Th differentiation. Similarly, the gut microbiota regulates the development of immune responses. Lastly, the key role of metabolism on T cells has also been demonstrated. This series of articles highlights some of the multiple links existing between environmental factors and T cell responses

Explorer Recombinant Ad 35 adenoviral proteins as potent modulators of human T cell activation

The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD4... more The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD46 also regulates the adaptive immune response by controlling T cell activation and differentiation. Co-engagement of the T cell receptor and CD46 notably drives T cell differentiation by switching production of IFNγ to secretion of anti-inflammatory IL-10. This regulatory pathway is altered in several chronic inflammatory diseases highlighting its key role for immune homeostasis. The manipulation of the CD46 pathway may therefore provide a powerful means to regulate immune responses. Herein, we investigated the effect of recombinant proteins derived from the fiber knob of the adenovirus serotype 35 (Ad35) that uses CD46 as its entry receptor, on human T cell activation. We compared the effects of Ad35K++, engineered to exhibit enhanced affinity to CD46, and of Ad35K-, mutated in the binding site for CD46. Ad35K++ profoundly affects T cell activation by decreasing the levels of CD46 at the surface of primary T cells, and impairing T cell co-activation, shown by decreased CD25 expression, reduced proliferation and lower secretion of IL-10 and IFNγ. In contrast, Ad35K-acts a potent coactivator of T cells, enhancing T cell proliferation and cytokine production. These data show that recombinant Ad35 proteins are potent modulators of human T cell activation, and support their further development as potential drugs targeting T cell responses.

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CD46 glycosylation and its implication in autoimmunity

Immunology, 2014

Editorial: T Cell Regulation by the Environment

Frontiers in Immunology, 2015

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Tyrosine phosphorylation of the product of the c-cbl protooncogene is [corrected] induced after integrin stimulation

Experimental hematology, 1997

Integrin crosslinking on human B cells induces tyrosine phosphorylation of a set of proteins rang... more Integrin crosslinking on human B cells induces tyrosine phosphorylation of a set of proteins ranging from 105 to 130 kDa, among which is the focal adhesion kinase p125FAK. Here we show that the c-CBL protooncogene product p120c-CBL is a component of these substrates. beta 1 integrin stimulation of p120c-CBL phosphorylation was observed in both transformed and normal human B cells, and was inhibited by prior treatment of cells with cytochalasin B, which disrupts the actin network. In contrast, tyrosine phosphorylation of p120c-CBL following crosslinking of the B cell antigen receptor (BCR) was not affected by cytochalasin B. Integrin stimulation of the promegakaryocytic cell line MO7e also led to a cytoskeleton-dependent tyrosine phosphorylation of p120c-CBL. In MO7e cells, this stimulation was induced by ligation of either beta 1 or beta 2 integrin, whereas only by ligation of beta 1 integrin in B cells. Tyrosine phosphorylation of p120c-CBL links phosphatidylinositol-3 kinase (PI-3...

Monocyte:T‐cell interaction regulates human T‐cell activation through a CD28/CD46 crosstalk

Immunology & Cell Biology, 2015

T‐cell activation requires engagement of the T‐cell receptor and of at least one costimulatory mo... more T‐cell activation requires engagement of the T‐cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T‐cell activation was reported several decades ago and the molecular mechanisms involved have now been well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T‐cell differentiation from producing some IFNγ to secreting some potent anti‐inflammatory IL‐10, acquiring a so‐called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T‐cell activation and IL‐10 production. The observation that CD46 cleavage was reduced when PBMCs were costimulated compared with purified CD4+ T cells led us to hypothesize that interactions between different cell types within the PBMCs were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4+ T cells are cocultured with autologous mo...

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RNAi screen of human primary T cells reveals FLT3 as a new regulator of IL-10 production

Recombinant Ad35 adenoviral proteins as potent modulators of human T-cell activation

Immunology, 2014

The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD4... more The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD46 also regulates the adaptive immune response by controlling T-cell activation and differentiation. Co-engagement of the T-cell receptor and CD46 notably drives T-cell differentiation by switching production of interferon-c to secretion of anti-inflammatory interleukin-10. This regulatory pathway is altered in several chronic inflammatory diseases, highlighting its key role for immune homeostasis. The manipulation of the CD46 pathway may therefore provide a powerful means to regulate immune responses. Herein, we investigated the effect of recombinant proteins derived from the fibre knob of the adenovirus serotype 35 (Ad35) that uses CD46 as its entry receptor, on human T-cell activation. We compared the effects of Ad35K++, engineered to exhibit enhanced affinity to CD46, and of Ad35KÀ, mutated in the binding site for CD46. Ad35K++ profoundly affects T-cell activation by decreasing the levels of CD46 at the surface of primary T cells, and impairing T-cell coactivation, shown by decreased CD25 expression, reduced proliferation and lower secretion of interleukin-10 and interferon-c. In contrast, Ad35KÀ acts a potent co-activator of T cells, enhancing T-cell proliferation and cytokine production. These data show that recombinant Ad35 proteins are potent modulators of human T-cell activation, and support their further development as potential drugs targeting T-cell responses.

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Explorer Calcitriol modulates the CD 46 pathway in T cells

The complement regulator CD46 is a costimulatory molecule for human T cells that induces a regula... more The complement regulator CD46 is a costimulatory molecule for human T cells that induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 costimulation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D can exert a direct effect on T cells, and may be beneficial in several pathologies, including MS. In this pilot study, we examined whether active vitamin D (1,25(OH)2D3 or calcitriol) could modulate the CD46 pathway and restore IL-10 production by CD46-costimulated CD4+ T cells from patients with MS. In healthy T cells, calcitriol profoundly affects the phenotype of CD46-costimulated CD4+ T cells, by increasing the expression of CD28, CD25, CTLA-4 and Foxp3 while it concomitantly decreased CD46 expression. Similar trends were observed in MS CD4+ T cells except for CD25 for which a striking opposite effect was observed: while CD25 was normally induced on MS T cells by CD46 costimulation, addit...

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Immune complex-induced apoptosis and concurrent immune complex clearance are anti-inflammatory neutrophil functions

Cell Death & Disease

Persistent neutrophilic inflammation drives host damage in autoimmune diseases that are character... more Persistent neutrophilic inflammation drives host damage in autoimmune diseases that are characterized by abundant immune complexes. Insoluble immune complexes (iICs) potently activate pro-inflammatory neutrophil effector functions. We and others have shown that iICs also promote resolution of inflammation via stimulation of neutrophil apoptosis. We demonstrate here that iICs trigger FcγRIIa-dependent neutrophil macropinocytosis, leading to the rapid uptake, and subsequent degradation of iICs. We provide evidence that concurrent iIC-induced neutrophil apoptosis is distinct from phagocytosis-induced cell death. First, uptake of iICs occurs by FcγRII-stimulated macropinocytosis, rather than phagocytosis. Second, production of reactive oxygen species, but not iIC-internalization is a pre-requisite for iIC-induced neutrophil apoptosis. Our findings identify a previously unknown mechanism by which neutrophils can remove pro-inflammatory iICs from the circulation. Together iIC clearance an...

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Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis

Frontiers in Immunology

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in... more Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of ...

A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites

The Journal of Immunology

The anthelmintic drug Praziquantel promotes human Tr1 differentiation

Immunology and Cell Biology

Anne L Astier

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