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Dive into the research topics where Iliyan D. Iliev is active.

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Featured researches published by Iliyan D. Iliev.


Science | 2012

Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis

Iliyan D. Iliev; Vincent Funari; Kent D. Taylor; Quoclinh Nguyen; Christopher N. Reyes; Samuel P. Strom; Jordan Brown; Courtney A. Becker; Phillip Fleshner; Marla Dubinsky; Jerome I. Rotter; Hanlin L. Wang; Dermot McGovern; Gordon D. Brown; David M. Underhill

The Mycobiome In the past few years, much attention has been given to the trillions of bacterial inhabitants in our guts and the myriad of ways in which they influence our overall health. But what about fungi? Iliev et al. (p. 1314) now report that mice and humans, along with several other mammals, contain a resident intestinal population of fungi. Deletion of Dectin-1, which acts as a major innate immune sensor for fungi, led to enhanced susceptibility and worse pathology in a chemically induced model of colitis in mice. A polymorphism in the gene that encodes Dectin-1 has been observed in patients with ulcerative colitis, which hints that, besides the traditional bacterial microbiome, alterations in the “mycobiome” may also play a role in health and disease. Mammals contain resident fungal intestinal populations that influence disease susceptibility. The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the “mycobiome”) that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.


Mucosal Immunology | 2009

Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning

Iliyan D. Iliev; Erika Mileti; Gianluca Matteoli; Marcello Chieppa; Maria Rescigno

Intestinal dendritic cells (DCs) have been shown to display specialized functions, including the ability to promote gut tropism to lymphocytes, to polarize noninflammatory responses, and to drive the differentiation of adaptive Foxp3+ regulatory T (Treg) cells. However, very little is known about what drives the mucosal phenotype of DCs. Here, we present evidence that the local microenvironment, and in particular intestinal epithelial cells (ECs), drive the differentiation of Treg-cell-promoting DCs, which counteracts Th1 and Th17 development. EC-derived transforming growth factor-β (TGF-β) and retinoic acid (RA), but not thymic stromal lymphopoietin (TSLP), were found to be required for DC conversion. After EC contact, DCs upregulated CD103 and acquired a tolerogenic phenotype. EC-conditioned DCs were capable of inducing de novo Treg cells with gut-homing properties that when adoptively transferred, protected mice from experimental colitis. Thus, we have uncovered an essential mechanism in which EC control of DC function is required for tolerance induction.


Gut | 2009

Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.

Iliyan D. Iliev; Ilaria Spadoni; Erika Mileti; Gianluca Matteoli; Angelica Sonzogni; Gianluca M. Sampietro; D. Foschi; Flavio Caprioli; Giuseppe Viale; Maria Rescigno

Objective: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (Treg) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. Methods: Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn’s disease and analysed for their ability to induce Treg cell differentiation. In some cases, transforming growth factor β (TGFβ), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103− DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in Treg cell differentiation experiments. Results: It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ Treg cells. This control was lost in patients with Crohn’s disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive Treg cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. Conclusions: A population of tolerogenic CD103+ DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive Treg cell development.


Gut | 2010

Gut CD103 + dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction

Gianluca Matteoli; Elisa Mazzini; Iliyan D. Iliev; Erika Mileti; Francesca Fallarino; Paolo Puccetti; Marcello Chieppa; Maria Rescigno

Objective CD103+ gut dendritic cells (DCs) have been shown to be required for de novo conversion of adaptive T regulatory (Treg) cells. Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in tryptophan catabolism that is expressed by DCs isolated from tumour-draining lymph nodes. IDO-expressing DCs sustain and differentiate Tregs. The aim of this study was to investigate the expression and the possible physiological role of IDO in the tolerogenic properties of intestinal DCs. Design The expression level of IDO in CD103+ and CD103− DCs was analysed by qRT-PCR, western blot and immunofluorescence. CD103+ and CD103− DCs were sorted from mesenteric lymph nodes (MLNs) and the small intestinal lamina propria, and the role of IDO in the conversion of Tregs and Th effector cell development was evaluated via specific inhibition or gene deletion. Oral tolerance, experimental colitis and T cell differentiation in vivo were assessed upon IDO inactivation. Results We show that, primarily, CD103+ but not CD103− gut DCs express IDO whose inhibition results in reduced CD4+Foxp3+ T regulatory cell conversion and enhanced T cell proliferation. When IDO was inhibited or genetically deleted there was an increase in Th1 and Th17 differentiation both in vitro and in vivo. Finally, in vivo IDO blockade affected the development of Tregs specific for orally administered antigens, impaired oral tolerance induction and exacerbated colitis. Conclusions We identified a new IDO-dependent pathway leading to acquisition of tolerogenic functions in mucosal CD103-expressing DCs, indicating IDO as a possible therapeutic target for gut disorders.


Nature Reviews Immunology | 2014

The mycobiota: interactions between commensal fungi and the host immune system.

David M. Underhill; Iliyan D. Iliev

The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.


PLOS ONE | 2009

Comparison of the Immunomodulatory Properties of Three Probiotic Strains of Lactobacilli Using Complex Culture Systems: Prediction for In Vivo Efficacy

Erika Mileti; Gianluca Matteoli; Iliyan D. Iliev; Maria Rescigno

Background While the use of probiotics to treat or prevent inflammatory bowel disease (IBD) has been proposed, to this point the clinical benefits have been limited. In this report we analyzed the immunological activity of three strains of Lactobacillus to predict their in vivo efficacy in protecting against experimental colitis. Methodology/Principal Findings We compared the immunological properties of Lactobacillus plantarum NCIMB8826, L. rhamnosus GG (LGG), L. paracasei B21060 and pathogenic Salmonella typhimurium (SL1344). We studied the stimulatory effects of these different strains upon dendritic cells (DCs) either directly by co-culture or indirectly via conditioning of an epithelial intermediary. Furthermore, we characterized the effects of these strains in vivo using a Dextran sulphate sodium (DSS) model of colitis. We found that the three strains exhibited different abilities to induce inflammatory cytokine production by DCs with L. plantarum being the most effective followed by LGG and L. paracasei. L. paracasei minimally induced the release of cytokines, while it also inhibited the potential of DCs to both produce inflammatory cytokines (IL-12 and TNF-α) and to drive Th1 T cells in response to Salmonella. This effect on DCs was found under both direct and indirect stimulatory conditions – i.e. mediated by epithelial cells - and was dependent upon an as yet unidentified soluble mediator. When tested in vivo, L. plantarum and LGG exacerbated the development of DSS-induced colitis and caused the death of treated mice, while, conversely L. paracasei was protective. Conclusions We describe a new property of probiotics to either directly or indirectly inhibit DC activation by inflammatory bacteria. Moreover, some immunostimulatory probiotics not only failed to protect against colitis, they actually amplified the disease progression. In conclusion, caution must be exercised when choosing a probiotic strain to treat IBD.


Journal of Experimental Medicine | 2007

The yin and yang of intestinal epithelial cells in controlling dendritic cell function

Iliyan D. Iliev; Gianluca Matteoli; Maria Rescigno

Recent work suggests that dendritic cells (DCs) in mucosal tissues are “educated” by intestinal epithelial cells (IECs) to suppress inflammation and promote immunological tolerance. After attack by pathogenic microorganisms, however, “non-educated” DCs are recruited from nearby areas, such as the dome of Peyers patches (PPs) and the blood, to initiate inflammation and the ensuing immune response to the invader. Differential epithelial cell (EC) responses to commensals and pathogens may control these two tolorogenic and immunogenic functions of DCs.


Cellular Microbiology | 2005

Strong immunostimulation in murine immune cells by Lactobacillus rhamnosus GG DNA containing novel oligodeoxynucleotide pattern.

Iliyan D. Iliev; Haruki Kitazawa; Takeshi Shimosato; Shinichiro Katoh; Hirotsugu Morita; Fang He; Masataka Hosoda; Tadao Saito

Whole cells, cell wall components and some soluble factors from Lactobacillus rhamnosus GG (LGG) are known to invoke immune responses as they interact with animal and human immune cells. In the present study, we found that chromosomal DNA from LGG is a potent inducer of splenic B cell proliferation, CD86/CD69 expression and cytokine production in mice. In the genomic DNA of LGG we discovered TTTCGTTT oligodeoxynucleotide (ODN) ID35, which has a potent activity in a number of immunostimulatory assays. Phosphorothioate backbone is not required for the activity of ID35. The ODN ID35 showed levels of activity comparable with those induced by the murine prototype ODN 1826 in B cell proliferation, CD86/CD69 expression, interleukin (IL)‐6, IL‐12, IL‐18, interferon gamma (IFN‐γ) and tumour necrosis factor alpha (TNF‐α) mRNA expression and IFN‐γ/IL‐12p70 protein production assays. Additionally, ID35 appeared to be equally active in both murine and human immune cells. These stimulatory effects are due to TTTCGTTT motif located in the 5′ end of ID35. In this study we demonstrate for a first time that, DNA from LGG is a factor of immunobiotic activity. Furthermore, ODN ID35 is the first ODN, with such a strong immunostimulatory activity to be found in immunobiotic bacterial DNA.


Nature Immunology | 2015

The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor

Corey R. Seehus; Parinaz Aliahmad; Brian de la Torre; Iliyan D. Iliev; Lindsay Spurka; Vincent Funari; Jonathan Kaye

Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage–restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.Diverse innate lymphoid cell (ILC) subtypes have been defined, based on effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways leading to ILC lineage specification remain poorly characterized. Here we demonstrate that transcriptional regulator TOX is required for the in vivo differentiation of common lymphoid progenitors to ILC lineage-restricted cells. In vitro modeling demonstrates that TOX deficiency results in early defects in progenitor cell survival or expansion as well as later stage ILC differentiation. In addition, comparative transcriptome analysis of bone marrow progenitors reveals that TOX-deficient cells fail to upregulate many aspects of the ILC gene program, including Notch gene targets, implicating TOX as a key determinant of early ILC lineage specification.


Nature Immunology | 2017

Regulation of inflammation by microbiota interactions with the host.

J. Magarian Blander; Randy S. Longman; Iliyan D. Iliev; Gregory F. Sonnenberg; David Artis

The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.

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David M. Underhill

Cedars-Sinai Medical Center

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Maria Rescigno

European Institute of Oncology

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Vincent Funari

Cedars-Sinai Medical Center

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Gianluca Matteoli

European Institute of Oncology

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Erika Mileti

European Institute of Oncology

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